[Show abstract][Hide abstract] ABSTRACT: There is increasing evidence that exposure of developing brains in animals, including nonhuman primates, to commonly-utilized anesthetic agents may cause adverse effects on cognition and behavior. In this paper, we summarize our methodology for a population-based, propensity-matched study to evaluate possible anesthesia-related sequelae in preschool children when evaluated in elementary or high school. A cohort of all children born in Olmsted County, Minnesota between the years 1994-2007 who are currently local residents has been identified. Existing medical records are being used to identify all episodes of exposure to general anesthesia prior to the age of 3 years (i.e., prior to their 3rd birthday). Children with multiple, single, and no anesthesia exposure are sampled for testing between the ages of 8-12 years or 15-19 years during the period 2012-2016. To match children in different exposure groups as closely as possible, sampling is guided by propensity-matching for the likelihood of receiving anesthesia. Selected children are invited to participate in a single 4-hour session of neuropsychological testing, including the National Center for Toxicological Research-Operant Test Battery, which has been used to study anesthetic neurotoxicity in nonhuman primates. The results of this testing will be compared among children with different anesthetic exposure histories. The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks.
[Show abstract][Hide abstract] ABSTRACT: Background and objective:
There is ongoing concern that stimulant medications may adversely affect growth. In a sample of attention-deficit/hyperactivity disorder (ADHD) cases and controls from a population-based birth cohort, we assessed growth and the association between stimulant treatment and growth.
Subjects included childhood ADHD cases (N = 340) and controls (N = 680) from a 1976 to 1982 birth cohort (N = 5718). Height and stimulant treatment information were abstracted from medical records and obtained during a prospective, adult follow-up study. For each subject, a parametric penalized spline smoothing method modeled height over time, and the corresponding height velocity was calculated as the first derivative. Peak height velocity (PHV) age and magnitude were estimated from the velocity curves. Among stimulant-treated ADHD cases, we analyzed height Z scores at the beginning, at the end, and 24 months after the end of treatment.
Neither ADHD itself nor treatment with stimulants was associated with differences in magnitude of PHV or final adult height. Among boys treated with stimulants, there was a positive correlation between duration of stimulant usage before PHV and age at PHV (r = 0.21, P = .01). There was no significant correlation between duration of treatment and change in height Z scores (r = -0.08 for beginning vs end change, r = 0.01 for end vs 24 months later change). Among the 59 ADHD cases treated for ≥3 years, there was a clinically insignificant decrease in mean Z score from beginning (0.48) to end (0.33) of treatment (P = .06).
Our findings suggest that ADHD treatment with stimulant medication is not associated with differences in adult height or significant changes in growth.
[Show abstract][Hide abstract] ABSTRACT: Adolescents with attention-deficit/hyperactivity disorder (ADHD) are known to be at significantly greater risk for the development of substance use disorders (SUD) compared to peers. Impulsivity, which could lead to higher levels of drug use, is a known symptom of ADHD and likely accounts, in part, for this relationship. Other factors, such as a biologically increased susceptibility to substance dependence (addiction), may also play a role.
PLoS ONE 08/2014; 9(8):e105640. DOI:10.1371/journal.pone.0105640 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adverse neurodevelopmental outcomes are observed in up to 50% of infants after complex cardiac surgery. We sought to determine the association of perioperative anesthetic exposure with neurodevelopmental outcomes at age 12 months in neonates undergoing complex cardiac surgery and to determine the effect of brain injury determined by magnetic resonance imaging (MRI).
Retrospective cohort study of neonates undergoing complex cardiac surgery who had preoperative and 7-day postoperative brain MRI and 12-month neurodevelopmental testing with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Doses of volatile anesthetics (VAA), benzodiazepines, and opioids were determined during the first 12 months of life.
From a database of 97 infants, 59 met inclusion criteria. Mean ± sd composite standard scores were as follows: cognitive = 102.1 ± 13.3, language = 87.8 ± 12.5, and motor = 89.6 ± 14.1. After forward stepwise multivariable analysis, new postoperative MRI injury (P = 0.039) and higher VAA exposure (P = 0.028) were associated with lower cognitive scores. ICU length of stay (independent of brain injury) was associated with lower performance on all categories of the Bayley-III (P < 0.02).
After adjustment for multiple relevant covariates, we demonstrated an association between VAA exposure, brain injury, ICU length of stay, and lower neurodevelopmental outcome scores at 12 months of age. These findings support the need for further studies to identify potential modifiable factors in the perioperative care of neonates with CHD to improve neurodevelopmental outcomes.
[Show abstract][Hide abstract] ABSTRACT: To determine whether DHA supplementation improves the behavior of children with autism.
3 to 10 year old children with autism were randomized in a double-blind fashion to receive a supplement containing 200 mg of DHA or a placebo for 6 months. Parent and investigator Clinical Global Impressions-Improvement (CGI-I) scales were completed to rate changes in core symptoms of autism after 3 and 6 months. Parents completed the Child Development Inventory (CDI) and Aberrant Behavior Checklist (ABC), and both parents and teachers completed the Behavior Assessment Scale for Children (BASC) at enrollment and after 6 months.
48 children (40 [83%] male; mean age [SD] = 6.1 [2.0] years) were enrolled; 24 received DHA and 24 placebo. Despite a median 431% increase in total plasma DHA levels after 6 months, the DHA group was not rated as improved in core symptoms of autism compared to the placebo group on the CGI-I. Based on analysis of covariance models adjusted for the baseline rating scores, parents (but not teachers) provided a higher average rating of social skills on the BASC for the children in the placebo group compared to the DHA group (p = 0.04), and teachers (but not parents) provided a higher average rating of functional communication on the BASC for the children in the DHA group compared to the placebo group (p = 0.02).
Dietary DHA supplementation of 200 mg per day for 6 months does not improve the core symptoms of autism. Our results may have been limited by inadequate sample size.
Journal of pediatric gastroenterology and nutrition 12/2013; DOI:10.1097/MPG.0000000000000260 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and objective:
Previous studies suggest that former late preterm infants are at increased risk for learning and behavioral problems compared with term infants. These studies have primarily used referred clinical samples of children followed only until early school age. Our objective was to determine the cumulative incidence of attention deficit/hyperactivity disorder (ADHD) and learning disabilities (LD) in former late preterm versus term infants in a population-based birth cohort.
Subjects included all children born 1976 to 1982 in Rochester, MN who remained in the community after 5 years. This study focused on the comparison of subjects in 2 subgroups, late preterm (34 to <37 weeks) and term (37 to <42 weeks). School and medical records were available to identify individuals who met research criteria for ADHD and LD in reading, written language, and math. The Kaplan-Meier method was used to estimate the cumulative incidence of each condition by 19 years of age. Cox models were fit to evaluate the association between gestational age group and condition, after adjusting for maternal education and perinatal complications.
We found no statistically significant differences in the cumulative incidence of ADHD or LD between the late preterm (N = 256) versus term (N = 4419) groups: ADHD (cumulative incidence by age 19 years, 7.7% vs 7.2%; P = .84); reading LD (14.2% vs 13.1%; P = .57); written language LD (13.5% vs 15.7%; P = .36), and math LD (16.1% vs 15.5%; P = .89).
These data from a population-based birth cohort indicate that former late preterm infants have similar rates of LD and ADHD as term infants.
[Show abstract][Hide abstract] ABSTRACT: Objective:
We examined long-term outcomes of attention-deficit/hyperactivity disorder (ADHD) in a population-based sample of childhood ADHD cases and controls, prospectively assessed as adults.
Adults with childhood ADHD and non-ADHD controls from the same birth cohort (N = 5718) were invited to participate in a prospective outcome study. Vital status was determined for birth cohort members. Standardized mortality ratios (SMRs) were constructed to compare overall and cause-specific mortality between childhood ADHD cases and controls. Incarceration status was determined for childhood ADHD cases. A standardized neuropsychiatric interview was administered.
Vital status for 367 childhood ADHD cases was determined: 7 (1.9%) were deceased, and 10 (2.7%) were currently incarcerated. The SMR for overall survival of childhood ADHD cases versus controls was 1.88 (95% confidence interval [CI], 0.83-4.26; P = .13) and for accidents only was 1.70 (95% CI, 0.49-5.97; P = .41). However, the cause-specific mortality for suicide only was significantly higher among ADHD cases (SMR, 4.83; 95% CI, 1.14-20.46; P = .032). Among the childhood ADHD cases participating in the prospective assessment (N = 232; mean age, 27.0 years), ADHD persisted into adulthood for 29.3% (95% CI, 23.5-35.2). Participating childhood ADHD cases were more likely than controls (N = 335; mean age, 28.6 years) to have ≥1 other psychiatric disorder (56.9% vs 34.9%; odds ratio, 2.6; 95% CI, 1.8-3.8; P < .01).
Childhood ADHD is a chronic health problem, with significant risk for mortality, persistence of ADHD, and long-term morbidity in adulthood.
[Show abstract][Hide abstract] ABSTRACT: Objective:
This study reports the incidence of enuresis and encopresis among children with attention-deficit/hyperactivity disorder (ADHD) versus those without ADHD.
Subjects included 358 children (74.5% boys) with research-identified ADHD from a 1976 to 1982 population-based birth cohort (n = 5718) and 729 (75.2% boys) non-ADHD control subjects from the same birth cohort, matched by gender and age. All subjects were retrospectively followed from birth until a diagnosis of enuresis or encopresis was made or last follow-up before 18 years of age. The complete medical record for each subject was reviewed to obtain information on age of initial diagnosis of an elimination disorder, frequency and duration of symptoms, and identification of exclusionary criteria specified by DSM-IV, with confirmation of the diagnosis by expert consensus.
Children with ADHD were 2.1 (95% confidence interval [CI], 1.3-3.4; P = .002) times more likely to meet DSM-IV criteria for enuresis than non-ADHD controls; they were 1.8 (95% CI, 1.2-2.7; P = .006) times more likely to do so than non-ADHD controls when less stringent criteria for a diagnosis of enuresis were employed. Though not significant, children with ADHD were 1.8 (95% CI, 0.7-4.6; P = .23) times more likely to meet criteria for encopresis than non-ADHD controls. The relative risk was 2.0 (95% CI, 1.0-4.1; P = .05) when a less stringent definition for encopresis was utilized.
Children with ADHD are more likely than their peers without ADHD to develop enuresis with a similar trend for encopresis.
[Show abstract][Hide abstract] ABSTRACT: To determine the range of neurodevelopmental diagnoses associated with intermediate (45-54 repeats) and premutation (55-200 repeats) range cytosine-guanine-guanine fragile X expansions, the medical records of children with intermediate or premutation range expansions were retrospectively reviewed, and all neurodevelopmental diagnoses were abstracted. Twenty-nine children (9 female, 20 male; age, 13 months to 17 years) with intermediate (n = 25) or premutation (n = 4) range expansions were identified with neurodevelopmental diagnoses, including global developmental delay/intellectual disability (n = 15), language and learning disorders (n = 9), attention-deficit hyperactivity disorder (n = 5), epilepsy (n = 5), and motor disorders (n = 12), including 2 boys younger than 4 years of age with tremor and ataxia. Thus, children with intermediate or premutation range fragile X cytosine-guanine-guanine expansions may be more susceptible than children without such expansions to other processes, both genetic and environmental, that contribute to neurodevelopmental disability.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Neonates undergoing complex congenital heart surgery have a significant incidence of neurologic problems. Erythropoietin has antiapoptotic, antiexcitatory, and anti-inflammatory properties to prevent neuronal cell death in animal models, and improves neurodevelopmental outcomes in full-term neonates with hypoxic ischemic encephalopathy. We designed a prospective phase I/II trial of erythropoietin neuroprotection in neonatal cardiac surgery to assess safety and indicate efficacy.
Neonates undergoing surgery for D-transposition of the great vessels, hypoplastic left heart syndrome, or aortic arch reconstruction were randomized to 3 perioperative doses of erythropoietin or placebo. Neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development III was performed at age 12 months.
Fifty-nine patients received the study drug. Safety profile, including magnetic resonance imaging brain injury, clinical events, and death, was not different between groups. Three patients in each group died. Forty-two patients (22 in the erythropoietin group and 20 in the placebo group; 79% of survivors) returned for 12-month follow-up. In the group receiving erythropoietin, mean Cognitive Scale scores were 101.1 ± 13.6, Language Scale scores were 88.5 ± 12.8, and Motor Scale scores were 89.9 ± 12.3. In the group receiving placebo, Cognitive Scale scores were 106.3 ± 10.8 (P = .19), Language Scores were 92.4 ± 12.4 (P = .33), and Motor Scale scores were 92.6 ± 14.1 (P = .51).
Safety profile for erythropoietin administration was not different than placebo. Neurodevelopmental outcomes were not different between groups; however, this pilot study was not powered to definitively address this outcome. Lessons learned suggest optimized study design features for a larger prospective trial to definitively address the utility of erythropoietin for neuroprotection in this population.
The Journal of thoracic and cardiovascular surgery 10/2012; 146(1). DOI:10.1016/j.jtcvs.2012.09.046 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
In this study we report magnetic resonance imaging (MRI) brain injury and 12-month neurodevelopmental outcomes when regional cerebral perfusion (RCP) is used for neonatal aortic arch reconstruction.
Fifty-seven neonates receiving RCP during aortic arch reconstruction were enrolled in a prospective outcome study. RCP flows were determined by near-infrared spectroscopy and transcranial Doppler monitoring. Brain MRI was performed preoperatively and 7 days postoperatively. Bayley Scales of Infant Development III was performed at 12 months.
Mean RCP time was 71 ± 28 minutes (range, 5 to 121 minutes) and mean flow was 56.6 ± 10.6 mL/kg/min. New postoperative MRI brain injury was seen in 40% of patients. For 35 RCP patients at age 12 months, mean Bayley Scales III Composite standard scores were: Cognitive, 100.1 ± 14.6 (range, 75 to 125); Language, 87.2 ± 15.0 (range, 62 to 132); and Motor, 87.9 ± 16.8 (range, 58 to 121). Increasing duration of RCP was not associated with adverse neurodevelopmental outcomes.
Neonatal aortic arch repair with RCP using a neuromonitoring strategy results in 12-month cognitive outcomes that are at reference population norms. Language and motor outcomes are lower than the reference population norms by 0.8 to 0.9 standard deviations. The neurodevelopmental outcomes in this RCP cohort demonstrate that this technique is effective and safe in supporting the brain during neonatal aortic arch reconstruction.
The Annals of thoracic surgery 07/2012; 95(2). DOI:10.1016/j.athoracsur.2012.04.070 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Expectations for outcomes after the neonatal arterial switch operation (ASO) continue to change. This cohort study describes neurodevelopmental outcomes at age 12 months after neonatal ASO, and analyzes both modifiable and nonmodifiable factors for association with adverse outcomes.
Patients who underwent an ASO (n=30) were enrolled in a prospective outcome study, with comprehensive clinical data collection during the first 12 months of life. Brain magnetic resonance imaging was done preoperatively and 7 days postoperatively, and the Bayley Scales of Infant Development III was performed at age 12 months.
Ten of 30 patients (33%) had preoperative magnetic resonance imaging injury; 13 of 30 patients (43%) had new postoperative magnetic resonance imaging injury. Twenty patients (67%) had Bayley Scales of Infant Development III: Cognitive Composite standard score mean was 104.8±15.0, Language Composite standard score median was 90.0 (25th to 75th percentile, 83 to 94), and Motor Composite standard score mean was 92.3±14.2. Best subsets multivariable analysis found associations between lower preoperative and intraoperative cerebral oxygen saturation, preoperative magnetic resonance imaging brain injury, total bypass time, and total midazolam dose and lower Bayley Scales of Infant Development III scores at age 12 months.
At 12 months after ASO, neurodevelopmental outcome means were within normal population ranges. The new associations reported in this study between potentially modifiable perioperative factors and outcomes require investigations in larger patient cohorts. Beyond survival, which was 100% in this cohort, factors influencing quality of life including neurodevelopmental outcomes should be routinely investigated in studies of ASO patients.
The Annals of thoracic surgery 06/2012; 94(4):1250-1256. DOI:10.1016/j.athoracsur.2012.04.050 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: To evaluate associations between attention-deficit/hyperactivity disorder (ADHD) and comorbid psychiatric disorders using research-identified incident cases of ADHD and population-based controls.
Methods: Subjects included a birth cohort of all children born 1976–1982 remaining in Rochester, MN after age five (n = 5,718). Among them we identified 379 ADHD incident cases and 758 age-gender matched non-ADHD controls, passively followed to age 19 years. All psychiatric diagnoses were identified and abstracted, but only those confirmed by qualified medical professionals were included in the analysis. For each psychiatric disorder, cumulative incidence rates for subjects with and without ADHD were estimated using the Kaplan–Meier method. Corresponding hazard ratios (HR) were estimated using Cox models adjusted for gender and mother’s age and education at the subject’s birth. The association between ADHD and the likelihood of having an internalizing or externalizing disorder was summarized by estimating odds ratios (OR).
Results: Attention-deficit/hyperactivity disorder was associated with a significantly increased risk of adjustment disorders (HR = 3.88), conduct/oppositional defiant disorder (HR = 9.54), mood disorders (HR = 3.67), anxiety disorders (HR = 2.94), tic disorders (HR = 6.53), eating disorders (HR = 5.68), personality disorders (HR = 5.80), and substance-related disorders (HR = 4.03). When psychiatric comorbidities were classified on the internalization-externalization dimension, ADHD was strongly associated with coexisting internalizing/externalizing (OR = 10.6), or externalizing-only (OR = 10.0) disorders.
Conclusion: This population-based study confirms that children with ADHD are at significantly increased risk for a wide range of psychiatric disorders. Besides treating the ADHD, clinicians should identify and provide appropriate treatment for psychiatric comorbidities.
Journal of Child Psychology and Psychiatry 05/2012; 53(10):1036-43. DOI:10.1111/j.1469-7610.2012.02567.x · 6.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The relationship between visual sustained attention-discrimination and goal-directed search was evaluated using a visual discrimination and exploration (goal-directed search) paradigm and urinary excretion of catecholaminergic metabolites [dopamine (DA) and norepinephrine (NE)] in 6-12 year-old children (n=31) strictly selected and diagnosed with attention-deficit/hyperactivity disorder (ADHD) using diagnostic criteria and other objective indices. The Structured Clinical Interview (SCID) (DSM-IV) was used to formally diagnose ADHD in children. A cognitive laboratory test was used to assess visual sustained attention-discrimination and goal-directed search (Children Color Trails Test 1 and 2). Urinary excretion of DA and NE metabolites was measured via reversed high-pressure liquid chromatography (HPLC). Pearson product-moment correlations were used to investigate the relationship between visual sustained attention and goal-directed search and urinary catecholamine metabolites of DA and NE. The present findings revealed a positive and moderately significant relationship between visual sustained attention and visual exploration and catecholaminergic metabolite levels of NE and DA, according to expectation. Decreased visual sustained attention and goal-directed search was associated with decreased DA and NE metabolite levels. The present results are consistent with past research with children with ADHD and studies with primates examining the intricate and respective interaction between the Locus Coeruleus and visual sustained attention-discrimination and the Ventral Tegmental Area and goal-directed search (visual exploration) respectively modulated through NE and DA. Applied and theoretical issues associated with the present findings also are discussed addressing recent computer-generated analogues of action selection models within the context of the extant findings.
Journal of Pediatric Biochemistry 01/2012; 2(2):115-122. DOI:10.3233/JPB-2012-0049
[Show abstract][Hide abstract] ABSTRACT: Annually, millions of children are exposed to anesthetic agents that cause apoptotic neurodegeneration in immature animals. To explore the possible significance of these findings in children, we investigated the association between exposure to anesthesia and subsequent (1) learning disabilities (LDs), (2) receipt of an individualized education program for an emotional/behavior disorder (IEP-EBD), and (3) scores of group-administered achievement tests.
This was a matched cohort study in which children (N = 8548) born between January 1, 1976, and December 31, 1982, in Rochester, Minnesota, were the source of cases and controls. Those exposed to anesthesia (n = 350) before the age of 2 were matched to unexposed controls (n = 700) on the basis of known risk factors for LDs. Multivariable analysis adjusted for the burden of illness, and outcomes including LDs, receipt of an IEP-EBD, and the results of group-administered tests of cognition and achievement were outcomes.
Exposure to multiple, but not single, anesthetic/surgery significantly increased the risk of developing LDs (hazard ratio: 2.12 [95% confidence interval: 1.26-3.54]), even when accounting for health status. A similar pattern was observed for decrements in group-administered tests of achievement and cognition. However, exposure did not affect the rate of children receiving an individualized education program.
Repeated exposure to anesthesia and surgery before the age of 2 was a significant independent risk factor for the later development of LDs but not the need for educational interventions related to emotion/behavior. We cannot exclude the possibility that multiple exposures to anesthesia/surgery at an early age may adversely affect human neurodevelopment with lasting consequence.
[Show abstract][Hide abstract] ABSTRACT: This is one of six short papers that describe additional innovations to help integrate public health into medical education; these were featured in the "Patients and Populations: Public Health in Medical Education" conference. They represent relatively new endeavors or curricular components that had not been explored in prior publications. Although evaluation data are lacking, it was considered to be of value to medical educators to share a brief description of the collaboration between the Division of Preventive, Occupational, and Aerospace Medicine and the Department of Pediatrics at Mayo Clinic to integrate a preventive medicine-public health curriculum into the pediatric residency.
American journal of preventive medicine 10/2011; 41(4 Suppl 3):S314-6. DOI:10.1016/j.amepre.2011.05.022 · 4.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We determined the incidence of written-language disorder (WLD) among children with and without attention-deficit/hyperactivity disorder (ADHD) in a population-based birth cohort.
Subjects included a birth cohort of all children born in 1976-1982 who remained in Rochester, Minnesota, after 5 years of age (N = 5718). Information from medical, school, and private tutorial records was abstracted. Cumulative incidences of WLD with or without reading disability (RD), identified with any of 3 formulas, among children with and without ADHD and hazard ratios (HRs) were calculated.
For both genders, the cumulative incidence of WLD by 19 years of age was significantly higher for children with ADHD than for children without ADHD (boys: 64.5% vs 16.5%; girls: 57.0% vs 9.4%). The magnitude of association between ADHD and WLD with RD was significantly higher for girls than for boys (adjusted HR: girls: 9.8; boys: 4.2; P < .001). However, this was not true for WLD without RD (adjusted HR: girls: 7.4; boys: 6.6; P = .64).
ADHD is strongly associated with an increased risk of WLD (with or without RD) for both boys and girls. Girls with ADHD are at higher risk of having WLD with RD compared with boys with ADHD, whereas boys and girls are at the same risk of having WLD without RD.