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Evidence-based care of extremely preterm infants (<28 weeks’ gestation) depends heavily on research in which a primary outcome is infant neurodevelopmental impairment (NDI), yet it is unclear how well NDI in infancy predicts long-term NDI. In this study, we aim to assess the relationship between 2- and 10-year neurodevelopment using a well-known 2-year definition and a 10-year definition developed by an expert panel.METHODS:
Using data from the Extremely Low Gestational Age Newborn Study cohort, we classified 2-year NDI using definitions developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. We classified 10-year NDI using definitions developed by an expert panel, which added epilepsy and ASD at 10 years.RESULTS:
Of 1506 infants, 80% survived. Data sufficient to classify severity of NDI at both 2 and 10 years were available for 67% of survivors (n = 802). Among children classified as having moderate to severe NDI at 2 years, 63% had none to mild NDI at 10 years; among children classified as having profound NDI at 2 years, 36% had none to mild NDI at 10 years. Cohen’s statistic indicated minimal to fair agreement between NDI at 2 and 10 years (0.34, P < .001).CONCLUSIONS:
NDI in infancy, as defined in this study, only weakly predicts NDI in middle childhood. For the parents at risk for delivery of an extremely preterm infant, a hopeful message can be taken from our findings that one-third of surviving children classified as having profound NDI and nearly two-thirds of those classified as having moderate to severe NDI at 2 years had none to mild NDI at 10 years.
Breastfeeding is an evidence-based recommendation for all countries, but breastfeeding rates have been declining in many middle-income settings. One reason behind this decline is the perception that breastfeeding may not be necessary in modern urban settings, where clean water is available and alternative foods are abundant. We investigate the importance of breastfeeding for early childhood development in the modern urban context of São Paulo, Brazil.METHODS:
In our study, we used data from the ongoing prospective Western Region Birth cohort in São Paulo, Brazil. Children were recruited at birth and managed for 3 years. Durations of exclusive and mixed breastfeeding were our primary independent variables. Our secondary independent variable was an indicator for compliance with World Health Organization (WHO) breastfeeding recommendations. Our primary outcomes of interest were indicators of children’s physical, cognitive, language, and social-emotional development at 3 years of age. Adjusted estimates and 95% confidence intervals were calculated by using linear and logistic regression.RESULTS:
Complying with WHO recommendations to exclusively breastfeed for 6 months followed by complementary feeding until 2 years of age was associated with a 0.4-SD increase in overall child development (β: .38; confidence limit = 0.23 to 0.53), a 0.6-SD increase in height-for-age z score (β: .55; confidence limit = 0.31 to 0.79), and a 67% decrease in the odds of stunting (odds ratio = 0.33; 95% confidence interval = 0.20 to 0.54).CONCLUSIONS:
Our results suggest that even in settings with easy access to complementary foods, complying with WHO breastfeeding recommendations is important for healthy physical growth and cognitive development.
To assess infection rates predischarge and postdischarge in breast milk–fed newborns with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–positive mothers who were separated postdelivery from their mothers and discharged from the hospital. Also, we aim to evaluate breastfeeding rates predischarge and postdischarge.METHODS:
Nasopharyngeal swabs for SARS-CoV-2 were obtained from symptomatic and high-risk women in the delivery room. Mothers with positive SARS-CoV-2 test results were separated from the newborns. Newborns were screened within 48 hours of delivery, and anti-infectious guidelines were imparted to the mothers before discharge. Rescreening took place ≥14 days postdischarge. Data regarding SARS-CoV-2–positive household members and breastfeeding were obtained by follow-up phone calls.RESULTS:
A total of 73 newborns of SARS-CoV-2–positive mothers were born in Israel during the ~3-month period under study. Overall, 55 participated in this study. All neonates tested negative for the virus postdelivery. A total 74.5% of the neonates were fed unpasteurized expressed breast milk during the postpartum separation until discharge. Eighty-nine percent of the neonates were discharged from the hospital after their mothers were instructed in anti-infection measures. In 40% of the households, there were additional SARS-CoV-2–positive residents. A total of 85% of the newborns were breastfed postdischarge. Results for all 60% of the newborns retested for SARS-CoV-2 postdischarge were negative.CONCLUSIONS:
No viral infection was identified in neonates born to and separated from their SARS-CoV-2–positive mothers at birth and subsequently fed unpasteurized breast milk. All infants breastfed at home remained SARS-CoV-2 negative. These findings may provide insights regarding the redundancy of postpartum mother-newborn separation in SARS-CoV-2–positive women and, assuming precautions are adhered to, support the safety of breast milk.
Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options.METHODS:
Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of >500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children <5 years of age.RESULTS:
Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over early childhood at around half the rate of their typically developing peers; girls with a full mutation showed growth at around three-quarters of the rate of their typically developing peers. Although children with a premutation were mostly typical in their developmental profiles and trajectories, mild but significant delays in fine motor skills by 18 months were detected.CONCLUSIONS:
Children with the FMR1 gene full mutation demonstrate significant developmental challenges within the first 2 years of life, suggesting that earlier identification is needed to facilitate earlier implementation of interventions and therapeutics to maximize effectiveness.
To determine if maternal intrapartum group B Streptococcus (GBS) antibiotic prophylaxis is associated with increased risk of childhood asthma, eczema, food allergy, or allergic rhinitis.METHODS:
Retrospective cohort study of 14 046 children. GBS prophylaxis was defined as administration of intravenous penicillin, ampicillin, cefazolin, clindamycin, or vancomycin to the mother, ≥4 hours before delivery. Composite primary outcome was asthma, eczema, or food allergy diagnosis within 5 years of age, identified by diagnosis codes and appropriate medication prescription. Allergic rhinitis was defined by using diagnostic codes only and analyzed as a separate outcome. Analysis was a priori stratified by delivery mode and conducted by using Cox proportional hazards model adjusted for multiple confounders and covariates. Secondary analyses, restricted to children retained in cohort at 5 years’ age, were conducted by using multivariate logistic regression.RESULTS:
GBS prophylaxis was not associated with increased incidence of composite outcome among infants delivered vaginally (hazard ratio: 1.13, 95% confidence interval [CI]: 0.95–1.33) or by cesarean delivery (hazard ratio: 1.08, 95% CI: 0.88–1.32). At 5 years of age, among 10 404 children retained in the study, GBS prophylaxis was not associated with the composite outcome in vaginal (odds ratio: 1.21, 95% CI: 0.96–1.52) or cesarean delivery (odds ratio: 1.17, 95% CI: 0.88–1.56) cohorts. Outcomes of asthma, eczema, food allergy, separately, and allergic rhinitis were also not associated with GBS prophylaxis.CONCLUSIONS:
Intrapartum GBS prophylaxis was not associated with subsequent diagnosis of asthma, eczema, food allergy, or allergic rhinitis in the first 5 years of age.
A male individual aged 18 years with no significant past medical history presented with fever, headache, dry cough, and chest pain. On clinical examination, he had tachycardia and hypotension needing intravenous fluid resuscitation and inotropic support. A chest radiograph revealed streaky lung opacities, and he was treated with antibiotics for suspected community-acquired pneumonia complicated by septic shock. Significant elevation of cardiac enzymes was noted, and there was a continued need for inotropes to maintain normotension. He also developed intermittent bradycardia, with serial electrocardiograms showing first-degree atrioventricular block, low-voltage QRS complexes, and ST-T wave changes and telemetry demonstrating junctional and ventricular escape rhythm. A complete workup for sepsis and acute myocarditis were performed to find the etiologic agent. Intravenous immunoglobulins were started to treat myocarditis, with eventual clinical improvement. He was eventually diagnosed with an unusual etiology for his illness. He was noted to still have intermittent ventricular escape rhythm on electrocardiograms on follow-up 2 weeks after discharge but continues to remain asymptomatic and in good health.
A 56 US hospital collaborative, Improving Pediatric Sepsis Outcomes, has developed variables, metrics and a data analysis plan to track quality improvement (QI)–based patient outcomes over time. Improving Pediatric Sepsis Outcomes expands on previous pediatric sepsis QI efforts by improving electronic data capture and uniformity across sites.METHODS:
An expert panel developed metrics and corresponding variables to assess improvements across the care delivery spectrum, including the emergency department, acute care units, hematology and oncology, and the ICU. Outcome, process, and balancing measures were represented. Variables and statistical process control charts were mapped to each metric, elucidating progress over time and informing plan-do-study-act cycles. Electronic health record (EHR) abstraction feasibility was prioritized. Time 0 was defined as time of earliest sepsis recognition (determined electronically), or as a clinically derived time 0 (manually abstracted), identifying earliest physiologic onset of sepsis.RESULTS:
Twenty-four evidence-based metrics reflected timely and appropriate interventions for a uniformly defined sepsis cohort. Metrics mapped to statistical process control charts with 44 final variables; 40 could be abstracted automatically from multiple EHRs. Variables, including high-risk conditions and bedside huddle time, were challenging to abstract (reported in <80% of encounters). Size or type of hospital, method of data abstraction, and previous QI collaboration participation did not influence hospitals’ abilities to contribute data. To date, 90% of data have been submitted, representing 200 007 sepsis episodes.CONCLUSIONS:
A comprehensive data dictionary was developed for the largest pediatric sepsis QI collaborative, optimizing automation and ensuring sustainable reporting. These approaches can be used in other large-scale sepsis QI projects in which researchers seek to leverage EHR data abstraction.
Children with medical complexity (CMC) are commonly assisted by medical devices, which family caregivers are responsible for managing and troubleshooting in the home. Optimizing device use by maximizing the benefits and minimizing the complications is a critical goal for CMC but is relatively unexplored. In this study, we sought to identify and describe workarounds families have developed to optimize medical device use for their needs.METHODS:
We conducted 30 contextual inquiry interviews with families of CMC in homes. Interviews were recorded, transcribed, and analyzed for barriers and workarounds specific to medical device usage through a directed content analysis. We used observation notes and photographs to confirm and elaborate on interview findings.RESULTS:
We identified 4 barriers to using medical devices in the home: (1) the quantity and type of devices allotted do not meet family needs, (2) the device is not designed to be used in locations families require, (3) device use is physically or organizationally disruptive to the home, and (4) the device is not designed to fit the user. We also identified 11 categories of workarounds to the barriers.CONCLUSIONS:
Families face many barriers in using medical devices to care for CMC. Our findings offer rich narrative and photographic data revealing the ways in which caregivers work around these barriers. Future researchers should explore the downstream effects of these ubiquitous, necessary workarounds on CMC outcomes toward developing interventions that optimize device use for families.
Bilirubin screening before discharge is performed to identify neonates at risk for future hyperbilirubinemia. The American Academy of Pediatrics recommends using a graph of bilirubin levels by age (the Bhutani Nomogram) to guide follow-up and a different graph to determine phototherapy recommendations. Our objective was to evaluate predictive models that incorporate the difference between the last total serum bilirubin (TSB) before discharge and the American Academy of Pediatrics phototherapy threshold (-TSB) to predict a postdischarge TSB above the phototherapy threshold by using a single graph.METHODS:
We studied 148 162 infants born at ≥35 weeks’ gestation at 11 Kaiser Permanente Northern California facilities from 2012 to 2017 whose TSB did not exceed phototherapy levels and who did not receive phototherapy during the birth hospitalization. We compared 3 logistic models (-TSB; -TSB-Plus, which included additional variables; and the Bhutani Nomogram) by using the area under the receiver operating characteristic curve (AUC) in a 20% validation subset.RESULTS:
A total of 2623 infants (1.8%) exceeded the phototherapy threshold postdischarge. The predicted probability of exceeding the phototherapy threshold after discharge ranged from 56% for a predischarge -TSB 0 to 1 mg/dL below the threshold to 0.008% for -TSB >7 mg/dL below the threshold. Discrimination was better for the -TSB model (AUC 0.93) and the -TSB-Plus model (AUC 0.95) than for the Bhutani Nomogram (AUC 0.88).CONCLUSIONS:
The use of -TSB models had excellent ability to predict postdischarge TSB above phototherapy thresholds and may be simpler to use than the Bhutani Nomogram.
Prediction models can be a valuable tool in performing risk assessment of mortality in preterm infants.OBJECTIVE:
Summarizing prognostic models for predicting mortality in very preterm infants and assessing their quality.DATA SOURCES:
Medline was searched for all articles (up to June 2020).STUDY SELECTION:
All developed or externally validated prognostic models for mortality prediction in liveborn infants born <32 weeks’ gestation and/or <1500 g birth weight were included.DATA EXTRACTION:
Data were extracted by 2 independent authors. Risk of bias (ROB) and applicability assessment was performed by 2 independent authors using Prediction model Risk of Bias Assessment Tool.RESULTS:
One hundred forty-two models from 35 studies reporting on model development and 112 models from 33 studies reporting on external validation were included. ROB assessment revealed high ROB in the majority of the models, most often because of inadequate (reporting of) analysis. Internal and external validation was lacking in 41% and 96% of these models. Meta-analyses revealed an average C-statistic of 0.88 (95% confidence interval [CI]: 0.83–0.91) for the Clinical Risk Index for Babies score, 0.87 (95% CI: 0.81–0.92) for the Clinical Risk Index for Babies II score, and 0.86 (95% CI: 0.78–0.92) for the Score for Neonatal Acute Physiology Perinatal Extension II score.LIMITATIONS:
Occasionally, an external validation study was included, but not the development study, because studies developed in the presurfactant era or general NICU population were excluded.CONCLUSIONS:
Instead of developing additional mortality prediction models for preterm infants, the emphasis should be shifted toward external validation and consecutive adaption of the existing prediction models.
The prevalence of current electronic cigarette (e-cigarette) use has increased dramatically among US youth. It is unknown how the impact of policies to curb e-cigarette use might differ across rural and urban areas.METHODS:
Data were collected from an annual statewide survey of middle and high school students in Kansas. Multivariable logistic regression was performed to examine the temporal change in current e-cigarette use in 2018 and 2019 across rural and urban areas and across the areas with and without a Tobacco 21 (T21) policy that raises the minimum age of tobacco sales to 21 years.RESULTS:
Of 132 803 participants, the prevalence of current e-cigarette use increased from 8.2% in 2018 to 12.6% in 2019. The increase was larger in rural areas (from 6.7% in 2018 to 13.4% in 2019, difference = 6.7%) than in urban areas (9.8%–11.9%, difference = 2.1%), with a significant interaction effect of year x urbanicity/T21 group (P < .0001). In urban areas, e-cigarette use increased significantly for middle school students in T21 areas (3.3%–4.5%; P = .01) and all students in non-T21 areas (8.1%–12.0%; P < .0001). In rural areas, the increase in e-cigarette use was significant in both T21 and non-T21 areas for all students, but the increase was smaller in T21 (7.9%–10.8%, difference = 3.0%) than in non-T21 areas (6.5%–13.7%, difference = 7.1%).CONCLUSIONS:
In this study, we reported marked disparities in the increase of youth e-cigarette use, with a larger recent increase in rural than in urban areas. T21 policies appear to mitigate these increases in both rural and urban youth.
Squamous cell carcinoma (SCC) of the oral cavity is one of the most common malignancies of the head and neck. Risk factors for the development of SCC include infection with human papillomavirus (HPV), tobacco use, and alcohol use. HPV-positive SCC of the oral cavity is more commonly seen in young adult patients, whereas HPV-negative disease is more prevalent in older patients with histories of alcohol and tobacco use. We describe the case of a young adult with an extensive history of vaping using nicotine-delivery systems who was diagnosed with HPV-negative SCC that was rapidly progressive and fatal.
In rare instances, severe respiratory syncytial virus (RSV) infections of the lower respiratory tract can cause life-threatening extrapulmonary complications. In this report, we describe 4 previously healthy, term and late-preterm infants admitted to the PICU with respiratory failure due to RSV bronchiolitis who developed necrotizing enterocolitis shortly after admission. All infants exhibited progressive abdominal distention, had typical radiographic findings, and developed simple or complex ascites. In addition to being managed with broad-spectrum antibiotics and bowel rest, 1 infant was treated with colon resection and ileostomy, 2 had peritoneal drainage procedures for ascites, and one of those later developed small bowel strictures treated with delayed resection and anastomosis. Three were discharged from the hospital without further complications; 1 died of septic shock. In this case series, we describe development of necrotizing enterocolitis in otherwise healthy neonates with severe RSV disease in the absence of traditional risk factors. We hypothesize that a dysregulated proinflammatory response associated with severe RSV disease may alter intestinal blood flow and compromise barriers to bacterial translocation. Enteral feeding intolerance, septic ileus, and/or complex ascites may represent important clinical corollaries in these patients.
Arginine vasopressin (AVP)–mediated osmoregulatory disorders, such as diabetes insipidus (DI) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are common in the differential diagnosis for children with hypo- and hypernatremia and require timely recognition and treatment. DI is caused by a failure to concentrate urine secondary to impaired production of or response to AVP, resulting in hypernatremia. Newer methods of diagnosing DI include measuring copeptin levels; copeptin is AVP’s chaperone protein and serves as a surrogate biomarker of AVP secretion. Intraoperative copeptin levels may also help predict the risk for developing DI after neurosurgical procedures. Copeptin levels hold diagnostic promise in other pediatric conditions, too. Recently, expanded genotype and phenotype correlations in inherited DI disorders have been described and may better predict the clinical course in affected children and infants. Similarly, newer formulations of synthetic AVP may improve pediatric DI treatment. In contrast to DI, SIADH, characterized by inappropriate AVP secretion, commonly leads to severe hyponatremia. Contemporary methods aid clinicians in distinguishing SIADH from other hyponatremic conditions, particularly cerebral salt wasting. Further research on the efficacy of therapies for pediatric SIADH is needed, although some adult treatments hold promise for pediatrics. Lastly, expansion of home point-of-care sodium testing may transform management of SIADH and DI in children. In this article, we review recent developments in the understanding of pathophysiology, diagnostic workup, and treatment of better outcomes and quality of life for children with these challenging disorders.
A mother whose child has a chronic condition, such as a major congenital anomaly, often experiences poorer long-term health, including earlier mortality. Little is known about the long-term health of fathers of infants with a major congenital anomaly.METHODS:
In this population-based prospective cohort study, we used individual-linked Danish registry data. Included were all mothers and fathers with a singleton infant born January 1, 1986, to December 31, 2015. Cox proportional hazards regression was used to generate hazard ratios for all-cause and cause-specific mortality among mothers and fathers whose infant had an anomaly and fathers of unaffected infants, relative to mothers of unaffected infants (referent), adjusted for child’s year of birth, parity, parental age at birth, parental comorbidities, and sociodemographic characteristics.RESULTS:
In total, 20 952 of 965 310 mothers (2.2%) and 20 655 of 951 022 fathers (2.2%) had an infant with a major anomaly. Median (interquartile range) of parental follow-up was 17.9 (9.5 to 25.5) years. Relative to mothers of unaffected infants, mothers of affected infants had adjusted hazard ratios (aHRs) of death of 1.20 (95% confidence interval [CI]: 1.09 to 1.32), fathers of unaffected infants had intermediate aHR (1.62, 95% CI: 1.59 to 1.66), and fathers of affected infants had the highest aHR (1.76, 95% CI: 1.64 to 1.88). Heightened mortality was primarily due to cardiovascular and endocrine/metabolic diseases.CONCLUSIONS:
Mothers and fathers of infants with a major congenital anomaly experience an increased risk of mortality, often from preventable causes. These findings support including fathers in interventions to support the health of parental caregivers.
Two adolescent boys presented with acute acneiform eruptions in the setting of recent dupilumab administration. Subsequent investigation via direct scraping of pustules revealed live Demodex mite colonization of the face. These adolescent patients represent a population not commonly associated with Demodex folliculitis, and we theorize their baseline commensal Demodex mite population may have increased as a consequence of dupilumab-induced, focused immunomodulation. We recommend that pediatricians consider Demodex potentially etiologic in patients presenting with new onset acneiform or rosacea-like dermatoses in patients treated with dupilumab.
Presence of a syndrome (or association) is predictive of poor survival in esophageal atresia (EA). However, most reports rely on historical patient outcomes, limiting their usefulness when estimating risk for neonates born today. We hypothesized improved syndromic EA survival due to advances in neonatal care.METHODS:
A retrospective single-center review of survival in 626 consecutive patients with EA from 1980 to 2017 was performed. Data were collected for recognized risk factors: preterm delivery; birth weight <1500 g; major cardiac disease; vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL); and non-VACTERL syndromes. Cox proportional hazards regression models were used to evaluate temporal trends in survival with respect to year of birth and syndromic EA.RESULTS:
Overall, 87% of 626 patients with EA survived, ranging from 82% in the 1980s to 91% in the 2010s. After adjusting for confounders, syndromic EA survival did not improve during the study, with no association found between year of birth and survival (hazard ratio [HR] 0.98, 95% confidence interval [CI]: 0.95–1.01). Aside from lethal non-VACTERL syndromes, patients with nonlethal non-VACTERL syndromes (HR 6.85, 95% CI: 3.50–13.41) and VACTERL syndrome (HR 3.02, 95% CI: 1.66–5.49) had a higher risk of death than those with nonsyndromic EA.CONCLUSIONS:
Survival of patients with syndromic EA has not improved, and patients with non-VACTERL syndromes have the highest risk of death. Importantly, this is independent of syndrome lethality, birth weight, and cardiac disease. This contemporary survival assessment will enable more accurate perinatal counseling of parents of patients with syndromic EA.
Children seeking care in the emergency department (ED) for mental health conditions are at risk for prolonged length of stay (LOS). A more contemporary description of trends and visit characteristics associated with prolonged ED LOS at the national level is lacking in the literature. Our objectives were to (1) compare LOS trends for pediatric mental health versus non–mental health ED visits and (2) explore patient-level characteristics associated with prolonged LOS for mental health ED visits.METHODS:
We conducted an observational analysis of ED visits among children 6 to 17 years of age using the National Hospital Ambulatory Medical Care Survey (2005–2015). We assessed trends in rates of prolonged LOS and the association between prolonged LOS and demographic and clinical characteristics (race and ethnicity, payer type, and presence of a concurrent physical health diagnosis) using descriptive statistics and survey-weighted logistic regression.RESULTS:
From 2005 to 2015, rates of prolonged LOS for pediatric mental health ED visits increased over time from 16.3% to 24.6% (LOS >6 hours) and 5.3% to 12.7% (LOS >12 hours), in contrast to non–mental health visits for which LOS remained stable. For mental health visits, Hispanic ethnicity was associated with an almost threefold odds of LOS >12 hours (odds ratio 2.74; 95% confidence interval 1.69–4.44); there was no difference in LOS by payer type.CONCLUSIONS:
The substantial rise in prolonged LOS for mental health ED visits and disparity for Hispanic children suggest worsening and inequitable access to definitive pediatric mental health care. Policy makers and health systems should work to provide equitable and timely access to pediatric mental health care.
Universal screening for autism spectrum disorder (ASD) is recommended during pediatric primary care visits in the first 2 years of life. However, many children are missed by initial screening and not diagnosed with ASD until years later. Research efforts are underway to develop and evaluate new objective measures of risk for ASD that can be used in infancy, before symptoms emerge. Initial studies with these tests, particularly MRI-based screening for infants at high familial risk, have shown promise but have not yet been evaluated in clinical trials. We present the study design for a hypothetical clinical trial that would combine presymptomatic detection and intervention for ASD and consider, through commentaries from diverse perspectives, the ethical issues that should be anticipated in advance of beginning such trials. Commentators Drs Pruett and Piven address the social value of the proposed research and importance of researcher-bioethicist collaborations. Drs Estes and Wolff discuss the clinical potential and challenges of developing presymptomatic interventions for infants at risk for ASD. Dr Harrington takes a neurodiversity view of presymptomatic prediction and intervention and their implications for autistic identity and quality of life. Finally, Drs MacDuffie, Peay and Wilfond consider the potential risks and benefits that must be evaluated and weighed in the next phases of research on presymptomatic detection and intervention for ASD.