Adaptive expression of engrams by retroactive interference.

Long-term memories are stored as configurations of neuronal ensembles, termed engrams. Although investigation of engram cell properties and functionality in memory recall has been extensive, less is known about how engram cells are affected by forgetting. We describe a form of interference-based forgetting using an object memory behavioral paradigm. By using activity-dependent cell labeling, we show that although retroactive interference results in decreased engram cell reactivation during recall trials, optogenetic stimulation of the labeled engram cells is sufficient to induce memory retrieval. Forgotten engrams may be reinstated via the presentation of similar or related environmental information. Furthermore, we demonstrate that engram activity is necessary for interference to occur. Taken together, these findings indicate that retroactive interference modules engram expression in a manner that is both reversible and updatable. Inference may constitute a form of adaptive forgetting where, in everyday life, new perceptual and environmental inputs modulate the natural forgetting process.

Chronic intrahippocampal interleukin-1ß overexpression in adolescence impairs hippocampal neurogenesis but not neurogenesis-associated cognition.

Both neuroinflammation and adult hippocampal neurogenesis (AHN) are implicated in many neurodegenerative disorders as well as in neuropsychiatric disorders, which often become symptomatic during adolescence. A better knowledge of the impact that chronic neuroinflammation has on the hippocampus during the adolescent period could lead to the discovery of new therapeutics for some of these disorders. The hippocampus is particularly vulnerable to altered concentrations of the pro-inflammatory cytokine interleukin-1ß (IL-1ß), with elevated levels implicated in the aetiology of neurodegenerative disorders such as Alzheimer's and Parkinson's, and stress-related disorders such as depression. The effect of acutely and chronically elevated concentrations of hippocampal IL-1ß have been shown to reduce AHN in adult rodents. However, the effect of exposure to chronic overexpression of hippocampal IL-1ß during adolescence, a time of increased vulnerability, hasn't been fully interrogated. Thus, in this study we utilized a lentiviral approach to induce chronic overexpression of IL-1ß in the dorsal hippocampus of adolescent male Sprague Dawley rats for 5 weeks, during which time its impact on cognition and hippocampal neurogenesis were examined. A reduction in hippocampal neurogenesis was observed along with a reduced level of neurite branching on hippocampal neurons. However, there was no effect of IL-1ß overexpression on performance in pattern separation, novel object recognition or spontaneous alternation in the Y maze. Our study has highlighted that chronic IL-1ß overexpression in the hippocampus during the adolescent period exerts a negative impact on neurogenesis independent of cognitive performance, and suggests a degree of resilience of the adolescent hippocampus to inflammatory insult.

Human Studies of Anesthesia-Related Neurotoxicity in Children: A Narrative Review of Recent Additions to the Clinical Literature.

In 2017, the US Food and Drug Administration warned that exposure to anesthetic medicines for lengthy periods of time or over multiple surgeries may affect brain development in children aged less than 3 years. Since then, the clinical literature continues to find mixed evidence of pediatric anesthesia-related neurotoxicity. However, several new human studies provide strong evidence that a single short exposure to general anesthesia in young children does not cause detectable neurocognitive injury by neuropsychological testing. These newer findings are reassuring, but cannot be extrapolated to children who are deemed to be at highest risk of neurologic injury after anesthesia.

Differential effects of adolescent and adult-initiated exercise on cognition and hippocampal neurogenesis.

Adolescence is a critical period for postnatal brain maturation and thus a time when environmental influences may affect cognitive processes in later life. Exercise during adulthood has been shown to increase hippocampal neurogenesis and enhance cognition. However, the impact of exercise initiated in adolescence on the brain and behavior in adulthood is not fully understood. The aim of this study was to compare the impact of voluntary exercise that is initiated during adolescence or early adulthood on cognitive performance in hippocampal-dependent and -independent processes using both object-based and touchscreen operant paradigms. Adult (8 week) and adolescent (4 week) male Sprague-Dawley rats had access to a running wheel (exercise) or were left undisturbed (sedentary control) for 4 weeks prior to behavioral testing and for the duration of the experiment. Results from touchscreen-based tasks showed that reversal learning was enhanced by both adult and adolescent-initiated exercise, while only exercise that began in adolescence induced a subtle but transient increase in performance on a location discrimination task. Spontaneous alternation in the Y-maze was impaired following adolescent onset exercise, while object memory was unaffected by either adult or adolescent-initiated exercise. Adolescent-initiated exercise increased the number of hippocampal DCX cells, an indicator of neurogenesis. It also promoted the complexity of neurites on DCX cells, a key process for synaptic integration, to a greater degree than adult-initiated exercise. Together the data here show that exercise during the adolescent period compared to adulthood differentially affects cognitive processes and the development of new hippocampal neurons in later life.

Developmental Neurotoxicity: An Update.

In the section of "Developmental Neurotoxicity: An Update" of the Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) symposium 2018 the speakers presented the current literature in translational and clinical research. Dr. Brambrink spoke about translational research in anesthetic neurotoxicity, beginning with discovery in the rodent model, then focusing on evidence from nonhuman primates. Dr. Waspe applied the methodology of Adverse Outcome Pathways from the field of toxicology to developmental neurotoxicity of anesthetics. Dr. O'Leary presented relevant clinical studies that were published in 2017 divided by a focus on academic performance, clinical outcomes or diagnoses, or neuropsychological testing.

Hospital admission on weekends for patients who have surgery and 30-day mortality in Ontario, Canada: A matched cohort study.

BACKGROUND: Healthcare interventions on weekends have been associated with increased mortality and adverse clinical outcomes, but these findings are inconsistent. We hypothesized that patients admitted to hospital on weekends who have surgery have an increased risk of death compared with patients who are admitted and have surgery on weekdays. METHODS AND FINDINGS: This matched cohort study included 318,202 adult patients from Ontario health administrative and demographic databases, admitted to acute care hospitals from 1 January 2005 to 31 December 2015. A total of 159,101 patients who were admitted on weekends and underwent noncardiac surgery were classified by day of surgery (weekend versus weekday) and matched 1:1 to patients who both were admitted and had surgery on a weekday (Tuesday to Thursday); matching was based on age (in years), anesthesia basic unit value for the surgical procedure, median neighborhood household income quintile, resource utilization band (a ranking system of overall morbidity), rurality of home location, year of admission, and urgency of admission. Of weekend admissions, 16.2% (25,872) were elective and 53.9% (85,744) had surgery on the weekend of admission. The primary outcome was all-cause mortality within 30 days of the date of hospital admission. The 30-day all-cause mortality for patients admitted on weekends who had noncardiac surgery was 2.6% (4,211/159,101) versus 2.5% (3,901/159,101) for those who were admitted and had surgery on weekdays (adjusted odds ratio [OR] 1.05; 95% CI 1.00 to 1.11; P = 0.03). However, there was significant heterogeneity in the increased odds of death according to the urgency of admission and when surgery was performed (weekend versus weekday). For urgent admissions on weekends (n = 133,229), there was no significant increase in odds of mortality when surgery was performed on the weekend (adjusted OR 1.02; 95% CI 0.95 to 1.09; P = 0.7) or on a subsequent weekday (adjusted OR 1.05; 95% CI 0.98 to 1.12; P = 0.2) compared to urgent admissions on weekdays. Elective admissions on weekends (n = 25,782) had increased risk of death both when surgery was performed on the weekend (adjusted OR 3.30; 95% CI 1.98 to 5.49; P < 0.001) and when surgery was performed on a subsequent weekday (adjusted OR 2.70; 95% CI 1.81 to 4.03; P < 0.001). The main limitations of this study were the lack of data regarding reason for admission and cause of increased time interval from admission to surgery for some cases, the small number of deaths in some subgroups (i.e., elective surgery), and the possibility of residual unmeasured confounding from increased illness severity for weekend admissions. CONCLUSIONS: When patients have surgery during their hospitalization, admission on weekends in Ontario, Canada, was associated with a small but significant proportional increase in 30-day all-cause mortality, but there was significant heterogeneity in outcomes depending on the urgency of admission and when surgery was performed. An increased risk of death was found only for elective admissions on weekends; whether this is a function of patient-level factors or represents a true weekend effect needs to be further elucidated. These findings have potential implications for resource allocation in hospitals and the redistribution of elective surgery to weekends.

Differential effects of adolescent and adult-initiated voluntary exercise on context and cued fear conditioning.

Adolescence is a critical period for postnatal brain maturation and a time during which there is increased susceptibility to developing emotional and cognitive-related disorders. Exercise during adulthood has been shown to increase hippocampal plasticity and enhance cognition. However, the impact of exercise initiated in adolescence, on brain and behaviour in adulthood is not yet fully explored or understood. The aim of this study was to compare the impact of voluntary exercise that was initiated either during adolescence or early adulthood on cognitive performance in hippocampal and amygdala-dependent fear conditioning tasks in adulthood. Adult (eight weeks old) and adolescent (four weeks old) male Sprague Dawley rats had access to a running wheel (exercise) or were left undisturbed (sedentary control) for seven weeks. Adult-initiated exercise enhanced both contextual and cued fear conditioning, while conversely, exercise that began in adolescence did not affect performance in these tasks. These behaviours were accompanied by differential expression of plasticity-related genes in the hippocampus and amygdala in adulthood. Specifically, adolescent-initiated exercise increased the expression of an array of plasticity related genes in the hippocampus including BDNF, synaptophysin, Creb, PSD-95, Arc, TLX and DCX, while adult-initiated exercise did not affect hippocampal plasticity related genes. Together results show that exercise initiated during adolescence has a differential effect on hippocampal and amygdala-dependent behaviour and neuronal plasticity compared to when exercise was initiated in adulthood. These findings reinforce adolescence as a period during which environmental influences have a distinct impact on neuronal plasticity and cognition. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

Preoperative anemia increases the risk of red blood cell transfusion and prolonged hospital length of stay in children undergoing spine arthrodesis surgery.

BACKGROUND: Preoperative anemia is an important modifiable risk factor for red blood cell (RBC) transfusion in a variety of surgical populations. The primary objective of this study was to examine the association between preoperative anemia and i) transfusion of RBCs within 72 hours of surgery and ii) postoperative clinical outcomes in children undergoing spine arthrodesis surgery. STUDY DESIGN AND METHODS: We assembled a retrospective cohort of children included in the American College of Surgeons National Quality Improvement Program Pediatric database who underwent spine arthrodesis surgery from 2012 to 2016. Anemia was defined using age- and sex-specific hematocrit thresholds. Data collected included demographic and surgical characteristics, RBC transfusion within 72 hours, and 30-day postoperative outcomes (postoperative mechanical ventilation, infection, readmission, hospital length of stay, mortality). Multivariable logistic regression analyses were used to identify independent predictors of RBC transfusion and postoperative outcomes. RESULTS: We included 9,095 patients in the analysis. Preoperative anemia was present in 14% (n = 1,233) of the population and 67% (n = 6,135) of patients were transfused. Our multivariable logistic regression showed anemia, surgical time > 350 minutes, > 7 vertebral levels fused, neuromuscular disease, and cerebral palsy were all independent predictors of RBC transfusion. Preoperative anemia was also associated with prolonged hospital LOS (adjusted OR: 1.31, 95%CI: 1.11-1.54, p = 0.002). CONCLUSIONS: In this study of 9,095 children undergoing spine surgery, preoperative anemia was associated with an increased risk of RBC transfusion and prolonged LOS. Further studies are needed to determine if treatment of preoperative anemia can effectively reduce intraoperative RBC transfusion.

Influence of Surgical Procedures and General Anesthesia on Child Development Before Primary School Entry Among Matched Sibling Pairs.

Importance: Substantial preclinical evidence suggests that the developing brain is susceptible to injury from anesthetic drugs. Findings from clinical studies of the neurotoxic effects of anesthesia are mixed, but these effects can be influenced by unmeasured confounding from biological and environmental risk and protective factors on child development. Objective: To examine the association between surgical procedures that require general anesthesia before primary school entry and child development in biological siblings. Design, Setting, and Participants: This retrospective sibling-matched cohort study included sibling pairs aged 5 to 6 years with the same birth mother who had Early Development Instrument (EDI) data completed. The EDI is a population-based measure of child development that assesses children's readiness to learn in 5 major domains (physical health and well-being, social knowledge and competence, emotional health and maturity, language and cognitive development, and communication skills and general knowledge). All eligible children in public and Catholic schools in Ontario, Canada, from 2004 through 2012 were included. Data were analyzed from December 13, 2017, through July 27, 2018. Exposures: Surgical procedures that require general anesthesia from the date of birth to EDI completion. Main Outcomes and Measures: Early developmental vulnerability, defined as any major domain of the EDI in the lowest 10th percentile of the Ontario population. Results: Of the 187 226 eligible children for whom the EDI was completed, a total of 10 897 sibling pairs (21 794 children; 53.8% female; mean [SD] age, 5.7 [0.3] years) were subsequently identified, including 2346 with only 1 child exposed to surgery. No significant differences were found between exposed and unexposed children in early developmental vulnerability (697 of 3080 [22.6%] vs 3739 of 18 714 [20.0%]; adjusted odds ratio [aOR], 1.03; 95% CI, 0.98-1.14; P = .58) or for each of the 5 major EDI domains (aOR for language and cognitive development, 0.96 [95% CI, 0.80-1.14]; aOR for physical health and well-being, 1.09 [95% CI, 0.96-1.24]; aOR for social knowledge and competence, 0.98 [95% CI, 0.84-1.14]; aOR for emotional health and maturity, 0.98 [95% CI, 0.84-1.14]; and aOR for communication skills and general knowledge, 0.90 [95% CI, 0.77-1.05]), after adjusting for confounding factors (age at EDI completion, sex, mother's age at birth, and eldest sibling status). Conclusions and Relevance: In this provincial cohort study, children who had surgical procedures that require general anesthesia before primary school entry were not found to be at increased risk of adverse child development outcomes compared with their biological siblings who did not have surgery. These findings further support that anesthesia exposure in early childhood is not associated with detectable adverse child development outcomes.

Chronic interleukin-1ß in the dorsal hippocampus impairs behavioural pattern separation.

Understanding the long-term consequences of chronic inflammation in the hippocampus may help to develop therapeutic targets for the treatment of cognitive disorders related to stress, ageing and neurodegeneration. The hippocampus is particularly vulnerable to increases in the pro-inflammatory cytokine interleukin-1ß (IL-1ß), a mediator of neuroinflammation, with elevated levels implicated in the aetiology of neurodegenerative diseases such as Alzheimer's and Parkinson's, and in stress-related disorders such as depression. Acute increases in hippocampal IL-1ß have been shown to impair cognition and reduce adult hippocampal neurogenesis, the birth of new neurons. However, the impact of prolonged increases in IL-1ß, as evident in clinical conditions, on cognition has not been fully explored. Therefore, the present study utilized a lentiviral approach to induce long-term overexpression of IL-1ß in the dorsal hippocampus of adult male Sprague Dawley rats and examine its impact on cognition. Following three weeks of viral integration, pattern separation, a process involving hippocampal neurogenesis, was impaired in IL-1ß-treated rats in both object-location and touchscreen operant paradigms. This was coupled with a decrease in the number and neurite complexity of immature neurons in the hippocampus. Conversely, tasks involving the hippocampus, but not sensitive to disruption of hippocampal neurogenesis, including spontaneous alternation, novel object and location recognition were unaffected. Touchscreen operant visual discrimination, a cognitive task involving the prefrontal cortex, was largely unaffected by IL-1ß overexpression. In conclusion, these findings suggest that chronically elevated IL-1ß in the hippocampus selectively impairs pattern separation. Inflammatory-mediated disruption of adult hippocampal neurogenesis may contribute to the cognitive decline associated with neurodegenerative and stress-related disorders.

Anesthesia and the developing brain: A way forward for laboratory and clinical research.

All commonly used general anesthetics have been shown to cause neurotoxicity in animal models, including nonhuman primates. Opinion, however, remains divided over how cumulative evidence from preclinical and human studies in this field should be interpreted and its translation to current practices in pediatric anesthesia and surgery. A group of international experts in laboratory and clinical sciences recently convened in Genoa, Italy, to evaluate the current state of both laboratory and clinical research and discuss future directions for basic, translational, and clinical studies in this field. This paper describes those discussions and conclusions. A central goal identified was the importance of continuing to pursue laboratory research efforts to better understand the biological pathways underlying anesthesia neurotoxicity. The distinction between basic and translational experimental designs in this field was highlighted, and it was acknowledged that it will be important for future animal research to try to causally link structural changes with long-term cognitive abnormalities. While inherent limitations will continue to affect the ability of even large observational cohorts to determine if anesthesia impacts neurodevelopment or behavioral outcomes, the importance of conducting further large well-designed cohort studies was also emphasized. Adequately powered cohorts could clarify which populations are at increased risk, provide information on environmental and healthcare-related risk modifiers, and guide future interventional trials. If anesthetics cause structural or functional adverse neurological effects in young children, alternative or mitigating strategies need to be considered. While protective or mitigating strategies have been repeatedly studied in animals, there are currently no human data to support alternative anesthetic strategies in clinical practice. Lastly, it was noted that there is still considerable debate over the clinical relevance of anesthesia neurotoxicity, and the need to evaluate the impact of other aspects of perioperative care on neurodevelopment must also be considered.

A low-cost touchscreen operant chamber using a Raspberry Pi™.

The development of a touchscreen platform for rodent testing has allowed new methods for cognitive testing that have been back-translated from clinical assessment tools to preclinical animal models. This platform for cognitive assessment in animals is comparable to human neuropsychological tests such as those employed by the Cambridge Neuropsychological Test Automated Battery, and thus has several advantages compared to the standard maze apparatuses typically employed in rodent behavioral testing, such as the Morris water maze. These include improved translation of preclinical models, as well as high throughput and the automation of animal testing. However, these systems are relatively expensive, which can impede progress for researchers with limited resources. Here we describe a low-cost touchscreen operant chamber based on the single-board computer, Raspberry PiTM, which is capable of performing tasks similar to those supported by current state-of-the-art systems. This system provides an affordable alternative for cognitive testing in a touchscreen operant paradigm for researchers with limited funding.

Predicting Heparin Responsiveness in Children Before Cardiopulmonary Bypass: A Retrospective Cohort Study.

BACKGROUND: Inadequate or excess administration of unfractionated heparin for cardiopulmonary bypass (CPB) can cause significant harm. Age-dependent differences in the pharmacodynamics and pharmacokinetics of heparin contribute to increased variability of heparin responsiveness in children. The aims of the current study were to (1) examine the correlation between predicted and observed heparin responsiveness in children before CPB measured using the Hemostasis Management System (HMS) Plus (Medtronic, Minneapolis, MN), (2) describe age-specific reference intervals for heparin sensitivity index (HSI) observed in children, and (3) test predictive models of HSI using preoperative clinical and laboratory data. METHODS: In this retrospective cohort study, children (ages ≤17 years) who required therapeutic heparinization for CPB in a 40-month period between September 2010 and December 2013 were investigated. Children weighing ≥45 kg or with a height ≥142 cm were excluded. HSI was defined as the difference between activated clotting time after heparin administration and the baseline activated clotting time divided by the heparin-loading dose (IU) per kilogram. Lin's concordance correlation coefficient was used for the primary analysis of the relationship between predicted and observed HSI. Reference intervals were calculated for HSI using medians and 2.5% and 97.5% percentiles according to established guidelines for clinical and laboratory standards. Nonparametric regression analyses were used to model the relationship between HSI (dependent variable) and preoperative covariates (independent variables). RESULTS: A total of 1281 eligible children were included in the final analysis. Overall, there was a moderate correlation between predicted and observed HSI measured using HMS Plus System (rho_c = 0.46; 95% confidence interval, 0.41-0.50; P < .001). Sixty-five percent (829 of 1281) of predicted HSI values were less than observed. From adjusted regression models, HSI was best predicted by preoperative international normalized ratio, platelet count, and weight, but this model accounted for only 25% of the variance in HSI. CONCLUSIONS: In a large cohort of children, heparin responsiveness before CPB was not reliably predicted by either in vitro measurement using the HMS Plus System or commonly available preoperative clinical and laboratory data. We describe age-specific reference intervals for HSI in children, and we anticipate that these data will aid the identification of heparin resistance in this population.

Incidence of non-physiologically complex surgical procedures performed in children: an Ontario population-based study of health administrative data.

PURPOSE: Quantification of surgical procedures undertaken by hospitals is necessary for informing resource allocation and modelling healthcare services. Our objective was to quantify the incidence, similarity, and diversity of non-physiologically complex surgical procedures performed at pediatric specialist hospitals and other hospitals performing pediatric surgery. METHODS: We conducted a population-based cohort study of children aged 28 days to 18 yr who underwent surgery in the province of Ontario from 2007 to 2015 using healthcare administrative databases. We estimated the incidence of non-physiologically complex procedures (i.e., ≤ 7 basic units in the 2015 Ontario Health Insurance Plan Schedule of Benefits) performed in pediatric specialist hospitals and other hospitals performing pediatric surgery. We used Yue and Clayton's index and the effective number of common procedures (1/Herfindahl index) to quantify the similarity and diversity of pediatric surgical procedures performed in these hospital types. RESULTS: Overall, 830,830 pediatric surgical procedures were performed in 158 Ontario hospitals during the eight-year study period. Most surgical procedures performed at hospitals performing pediatric surgery were non-physiologically complex (vs 50%, P < 0.001). The incidence of non-physiologically complex procedures increased progressively each year at pediatric specialist hospitals and was associated with a reciprocal decline among the other hospitals. Comparing pediatric specialist hospitals with the other hospitals, the mean similarity index for non-physiologically complex procedures was less than moderate (0.52; 95% confidence interval [CI], 0.51 to 0.54). The mean effective number of common non-physiologically complex procedures (i.e., the diversity) among the pediatric specialist hospitals was greater than at the other 154 hospitals performing pediatric surgery (65.3 vs 21.8 procedures, respectively; mean difference, 43.5; 95% CI, 42.2 to 44.8; P < 0.001). CONCLUSIONS: Non-physiologically complex procedures have progressively migrated to pediatric specialist hospitals from other hospitals in Ontario. Specialty pediatric hospitals are principally dissimilar from other hospitals performing pediatric surgery based not on physiological complexity, but on their diversity. These findings suggest that some types of surgical procedures may be redistributed from specialist pediatric hospitals to other hospitals performing pediatric surgery. TRIAL REGISTRATION: www.clinicaltrials.gov , number NCT03144544. Registered 2 May 2016.

The Association Between Cyanosis and Thromboelastometry (ROTEM) in Children With Congenital Heart Defects: A Retrospective Cohort Study.

BACKGROUND: Children with congenital heart defects (CHD) have quantitative and qualitative differences in coagulation compared with healthy children. Secondary to polycythemia and increased deformability of red blood cells, cyanosis may be an important confounding factor for altered whole-blood coagulation in this population with potential implications for interpreting intraoperative thromboelastometry (TEM) for children with CHD undergoing major surgery. The primary aim of the study was to evaluate the association between cyanosis in children with CHD and measures of whole-blood coagulation determined using TEM (ROTEM [Tem International, GmbH, Munich, Germany]). METHODS: In this retrospective cohort study, children who underwent congenital cardiac surgery in a 12-month period between April 2014 and 2015 were investigated. Children who were receiving antiplatelet or anticoagulant medications in the preoperative period were excluded. Eligible children were categorized by the presence of cyanosis, defined as an oxyhemoglobin concentration ≤85%. Multivariable linear regression analyses were used to determine the relationship between cyanosis and TEM outcomes (primary outcome, fibrinogen/fibrin polymerization [FibTEM] maximal clot firmness [MCF]) adjusting for potential confounding factors. RESULTS: Three hundred forty-five TEM profiles from 320 children were included in the cohort for analysis. Twenty-two percent (76/345) of children had cyanotic CHD. Clot firmness measured using the FibTEM assay was decreased in cyanotic children compared with noncyanotic children, median difference (95% confidence interval) interim [2 (0-3) mm; P = .01], and maximal [2 (1-3) mm; P = .01] clot firmness. The association between cyanosis and fibrinogen/fibrin polymerization clot firmness was not significant (A10, P = .7; MCF, P = .7) after adjusting for confounding factors (hematocrit, platelet count, and sex). There was a significant association between cyanosis and intrinsically activated clot firmness (A10, P = .03; MCF, P = .02), but not other TEM outcomes, after adjusting for confounding factors. CONCLUSIONS: Cyanotic children had decreased clot firmness in the fibrinogen/fibrin polymerization component of the clot compared with noncyanotic children, but the association between cyanosis and clot firmness was accounted for by differences in hematocrit, platelet count, and sex between groups. These findings will help guide the identification and treatment of coagulopathy in this vulnerable population.

A Population-based Study Evaluating the Association between Surgery in Early Life and Child Development at Primary School Entry.

BACKGROUND: It is unclear whether exposure to surgery in early life has long-term adverse effects on child development. The authors aimed to investigate whether surgery in early childhood is associated with adverse effects on child development measured at primary school entry. METHODS: The authors conducted a population-based cohort study in Ontario, Canada, by linking provincial health administrative databases to children's developmental outcomes measured by the Early Development Instrument (EDI). From a cohort of 188,557 children, 28,366 children who underwent surgery before EDI completion (age 5 to 6 yr) were matched to 55,910 unexposed children. The primary outcome was early developmental vulnerability, defined as any domain of the EDI in the lowest tenth percentile of the population. Subgroup analyses were performed based on age at first surgery (less than 2 and greater than or equal to 2 yr) and frequency of surgery. RESULTS: Early developmental vulnerability was increased in the exposed group (7,259/28,366; 25.6%) compared with the unexposed group (13,957/55,910; 25.0%), adjusted odds ratio, 1.05; 95% CI, 1.01 to 1.08. Children aged greater than or equal to 2 yr at the time of first surgery had increased odds of early developmental vulnerability compared with unexposed children (odds ratio, 1.05; 95% CI, 1.01 to 1.10), but children aged less than 2 yr at the time of first exposure were not at increased risk (odds ratio, 1.04; 95% CI, 0.98 to 1.10). There was no increase in odds of early developmental vulnerability with increasing frequency of exposure. CONCLUSIONS: Children who undergo surgery before primary school age are at increased risk of early developmental vulnerability, but the magnitude of the difference between exposed and unexposed children is small.