Association of Neonatal Glycemia with Neurodevelopmental Outcomes at 4.5 Years
TL;DR: Neonatal hypoglycemia was not associated with increased risk of combined neurosensory impairment at 4.5 years but was associated with a dose-dependent increasedrisk of poor executive function and visual motor function, even if not detected clinically, and may thus influence later learning.
Abstract: Importance Hypoglycemia is common during neonatal transition and may cause permanent neurological impairment, but optimal intervention thresholds are unknown. Objective To test the hypothesis that neurodevelopment at 4.5 years is related to the severity and frequency of neonatal hypoglycemia. Design, Setting, and Participants The Children With Hypoglycemia and Their Later Development (CHYLD) Study is a prospective cohort investigation of moderate to late preterm and term infants born at risk of hypoglycemia. Clinicians were masked to neonatal interstitial glucose concentrations; outcome assessors were masked to neonatal glycemic status. The setting was a regional perinatal center in Hamilton, New Zealand. The study was conducted from December 2006 to November 2010. The dates of the follow-up were September 2011 to June 2015. Participants were 614 neonates born from 32 weeks’ gestation with at least 1 risk factor for hypoglycemia, including diabetic mother, preterm, small, large, or acute illness. Blood and masked interstitial glucose concentrations were measured for up to 7 days after birth. Infants with hypoglycemia (whole-blood glucose concentration Exposures Neonatal hypoglycemic episode, defined as at least 1 consecutive blood glucose concentration less than 47 mg/dL, a severe episode ( Main Outcomes and Measures Cognitive function, executive function, visual function, and motor function were assessed at 4.5 years. The primary outcome was neurosensory impairment, defined as poor performance in one or more domains. Results In total, 477 of 604 eligible children (79.0%) were assessed. Their mean (SD) age at the time of assessment was 4.5 (0.1) years, and 228 (47.8%) were female. Those exposed to neonatal hypoglycemia (280 [58.7%]) did not have increased risk of neurosensory impairment (risk difference [RD], 0.01; 95% CI, −0.07 to 0.10 and risk ratio [RR], 0.96; 95% CI, 0.77 to 1.21). However, hypoglycemia was associated with increased risk of low executive function (RD, 0.05; 95% CI, 0.01 to 0.10 and RR, 2.32; 95% CI, 1.17 to 4.59) and visual motor function (RD, 0.03; 95% CI, 0.01 to 0.06 and RR, 3.67; 95% CI, 1.15 to 11.69), with highest risk in children exposed to severe, recurrent, or clinically undetected (interstitial episodes only) hypoglycemia. Conclusions and Relevance Neonatal hypoglycemia was not associated with increased risk of combined neurosensory impairment at 4.5 years but was associated with a dose-dependent increased risk of poor executive function and visual motor function, even if not detected clinically, and may thus influence later learning. Randomized trials are needed to determine optimal screening and intervention thresholds based on assessment of neurodevelopment at least to school age.
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Children's Hospital of Philadelphia1, Great Ormond Street Hospital2, McMaster University3, Boston Children's Hospital4, St Mary's Hospital5, University of Queensland6, University of Cape Town7, University of Liverpool8, Durham University9, French Institute of Health and Medical Research10, South University11, University of Cambridge12, University Hospital Southampton NHS Foundation Trust13, Nationwide Children's Hospital14, Erasmus University Medical Center15, All India Institute of Medical Sciences16, Radboud University Nijmegen17, Royal Children's Hospital18, Children's Hospital Los Angeles19, New York University20, Stony Brook University21, Apollo Hospitals22, Johns Hopkins University23, University of the West of England24, University of Iowa25, St. Jude Children's Research Hospital26, Cincinnati Children's Hospital Medical Center27, Seattle Children's28, University of British Columbia29, Centre national de la recherche scientifique30
TL;DR: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations.
Abstract: OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 52 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 49 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.
541 citations
Children's Hospital of Philadelphia1, Great Ormond Street Hospital2, McMaster University3, Boston Children's Hospital4, St Mary's Hospital5, University of Queensland6, University of Cape Town7, University of Liverpool8, Durham University9, South University10, French Institute of Health and Medical Research11, University of Cambridge12, University Hospital Southampton NHS Foundation Trust13, Nationwide Children's Hospital14, Erasmus University Medical Center15, All India Institute of Medical Sciences16, Radboud University Nijmegen17, Royal Children's Hospital18, University Health System19, Children's Hospital Los Angeles20, New York University21, Stony Brook University22, Apollo Hospitals23, Johns Hopkins University24, University of the West of England25, University of Iowa26, St. Jude Children's Research Hospital27, Cincinnati Children's Hospital Medical Center28, Seattle Children's29, University of British Columbia30, Centre national de la recherche scientifique31
TL;DR: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations.
Abstract: OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 52 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.
361 citations
TL;DR: Neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment that may become apparent at later ages and carefully designed randomized trials are required to determine the optimal management of neonates at risk of hypoglycemia with long-term follow-up at least to school age.
Abstract: Background Hypoglycaemia is the most common metabolic problem in neonates but there is no universally accepted threshold for safe blood glucose concentrations due to uncertainty regarding effects on neurodevelopment. Objective To systematically assess the association between neonatal hypoglycaemia on neurodevelopment outcomes in childhood and adolescence. Methods We searched MEDLINE, EMBASE, CINAHL, and PsycINFO from inception until February 2018. We included studies that reported one or more prespecified outcomes and compared children exposed to neonatal hypoglycaemia with children not exposed. Studies of neonates with congenital malformations, inherited metabolic disorders and congenital hyperinsulinism were excluded. Two authors independently extracted data using a customized form. We used ROBINS-I to assess risk of bias, GRADE for quality of evidence, and REVMAN for meta-analysis (inverse variance, fixed effects). Results 1,665 studies were screened, 61 reviewed in full, and 11 included (12 publications). In early childhood, exposure to neonatal hypoglycaemia was not associated with neurodevelopmental impairment (n = 1,657 infants; OR = 1.16, 95% CI = 0.86-1.57) but was associated with visual-motor impairment (n = 508; OR = 3.46, 95% CI = 1.13-10.57) and executive dysfunction (n = 463; OR = 2.50, 95% CI = 1.20-5.22). In mid-childhood, neonatal hypoglycaemia was associated with neurodevelopmental impairment (n = 54; OR = 3.62, 95% CI = 1.05-12.42) and low literacy (n = 1,395; OR = 2.04, 95% CI = 1.20-3.47) and numeracy (n = 1,395; OR = 2.04, 95% CI = 1.21-3.44). No data were available for adolescents. Conclusions Neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment that may become apparent at later ages. Carefully designed randomized trials are required to determine the optimal management of neonates at risk of hypoglycaemia with long-term follow-up at least to school age.
122 citations
TL;DR: In this article, the benefits of using antenatal corticosteroids for periviable deliveries in high-resource environments were evaluated. But, the randomized controlled trial data also did not strongly support the optimal interval from pregnancy onset to delivery of 1-7 days.
107 citations
TL;DR: In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold was noninferior to a traditional threshold with regard to psychomotor development at 18 months.
Abstract: BACKGROUND Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment. METHODS In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group. RESULTS Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death. CONCLUSIONS In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).
66 citations
References
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TL;DR: Preliminary findings suggest that the SDQ functions as well as the Rutter questionnaires while offering the following additional advantages: a focus on strengths as as difficulties; better coverage of inattention, peer relationships, and prosocial behaviour; a shorter format; and a single form suitable for both parents and teachers, perhaps thereby increasing parent-teacher correlations.
Abstract: A novel behavioural screening questionnaire, the Strengths and Difficulties Questionnaire (SDQ), was administered along with Rutter questionnaires to parents and teachers of 403 children drawn from dental and psychiatric clinics. Scores derived from the SDQ and Rutter questionnaires were highly correlated; parent-teacher correlations for the two sets of measures were comparable or favoured the SDQ. The two sets of measures did not differ in their ability to discriminate between psychiatric and dental clinic attenders. These preliminary findings suggest that the SDQ functions as well as the Rutter questionnaires while offering the following additional advantages: a focus on strengths as well as difficulties; better coverage of inattention, peer relationships, and prosocial behaviour; a shorter format; and a single form suitable for both parents and teachers, perhaps thereby increasing parent-teacher correlations.
11,877 citations
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...12 to <24 h 65 (13) [14-177] 465 63 (13) [14-177] 276 68 (13) [47-146]b 189 68 (14) [34-135]c 128...
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...≥48 h 76 (14) [20-207] 282 74 (14) [20-200] 197 81 (16) [47-207]b 85 79 (14) [34-177] 59...
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...24 to <48 h 68 (13) [11-169] 443 67 (13) [11-155] 271 70 (14) [47-169]b 172 70 (13) [38-132] 128...
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...Blood glucose concentration, mg/dL, mean (SD) [range]g <12 h 59 (13) [0-153] 469 54 (9) [0-153] 275 67 (13) [47-153]b 194 61 (13) [7-133]e 136...
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TL;DR: Correlational and regression analyses revealed that visual short-term and working memory were found to specifically predict math achievement at each time point, while executive function skills predicted learning in general rather than learning in one specific domain.
Abstract: This study examined whether measures of short-term memory, working memory, and executive functioning in preschool children predict later proficiency in academic achievement at 7 years of age (third year of primary school). Children were tested in preschool (M age = 4 years, 6 months) on a battery of cognitive measures, and mathematics and reading outcomes (from standardized, norm-referenced school-based assessments) were taken on entry to primary school, and at the end of the first and third year of primary school. Growth curve analyses examined predictors of math and reading achievement across the duration of the study and revealed that better digit span and executive function skills provided children with an immediate head start in math and reading that they maintained throughout the first three years of primary school. Visual-spatial short-term memory span was found to be a predictor specifically of math ability. Correlational and regression analyses revealed that visual short-term and working memory were found to specifically predict math achievement at each time point, while executive function skills predicted learning in general rather than learning in one specific domain. The implications of the findings are discussed in relation to further understanding the role of cognitive skills in different mathematical tasks, and in relation to the impact of limited cognitive skills in the classroom environment.
1,414 citations
Additional excerpts
...12 to <24 h 65 (13) [14-177] 465 63 (13) [14-177] 276 68 (13) [47-146]b 189 68 (14) [34-135]c 128...
[...]
...≥48 h 76 (14) [20-207] 282 74 (14) [20-200] 197 81 (16) [47-207]b 85 79 (14) [34-177] 59...
[...]
...24 to <48 h 68 (13) [11-169] 443 67 (13) [11-155] 271 70 (14) [47-169]b 172 70 (13) [38-132] 128...
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...Blood glucose concentration, mg/dL, mean (SD) [range]g <12 h 59 (13) [0-153] 469 54 (9) [0-153] 275 67 (13) [47-153]b 194 61 (13) [7-133]e 136...
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TL;DR: It is concluded that the requirement to learn and remember two rules is not in itself sufficient to account for the poor performance of the younger children in the experimental condition.
1,388 citations
Additional excerpts
...24 to <48 h 68 (13) [11-169] 443 67 (13) [11-155] 271 70 (14) [47-169]b 172 70 (13) [38-132] 128...
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...Blood glucose concentration, mg/dL, mean (SD) [range]g <12 h 59 (13) [0-153] 469 54 (9) [0-153] 275 67 (13) [47-153]b 194 61 (13) [7-133]e 136...
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TL;DR: Inhibitory control was significantly associated with internalization, both contemporaneously and as a predictor in the longitudinal sense.
Abstract: We examined inhibitory control as a quality of temperament that contributes to internalization. Children were assessed twice, at 26-41 months (N = 103) and at 43-56 months (N = 99), on repeated occasions, in multiple observational contexts and using parental reports. Comprehensive behavioral batteries incorporating multiple tasks were designed to measure inhibitory control at toddler and preschool age. They had good internal consistencies, corresponded with maternal ratings, and were developmentally sensitive. Individual children's performance was significantly correlated across both assessments, indicating stable individual differences. Girls surpassed boys at both ages. Children's internalization was observed while they were alone with prohibited objects, with a mundane chore, playing games that occasioned cheating, being induced to violate standards of conduct, and assessed using maternal reports. Inhibitory control was significantly associated with internalization, both contemporaneously and as a predictor in the longitudinal sense. The implications for considering children's temperament as a significant, yet often neglected contributor to developing internalization are discussed.
961 citations
Additional excerpts
...12 to <24 h 65 (13) [14-177] 465 63 (13) [14-177] 276 68 (13) [47-146]b 189 68 (14) [34-135]c 128...
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...24 to <48 h 68 (13) [11-169] 443 67 (13) [11-155] 271 70 (14) [47-169]b 172 70 (13) [38-132] 128...
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...Blood glucose concentration, mg/dL, mean (SD) [range]g <12 h 59 (13) [0-153] 469 54 (9) [0-153] 275 67 (13) [47-153]b 194 61 (13) [7-133]e 136...
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Book•
04 Jun 2000
TL;DR: The results of these studies provide the basis for a revision of the CCC theory that specifies more clearly the circumstances in which children will have difficulty using rules at various levels of complexity, provides a more detailed account of how to determine the complexity of rules required in a task, takes account of both the activation and inhibition of rules as a function of experience, and highlights the importance of taking intentionality seriously in the study of executive function.
Abstract: According to the Cognitive Complexity and Control (CCC) theory, the development of executive function can be understood in terms of age-related increases in the maximum complexity of the rules children can formulate and use when solving problems. This Monograph describes four studies (9 experiments) designed to test hypotheses derived from the CCC theory and from alternative theoretical perspectives on the development of executive function (memory accounts, inhibition accounts, and redescription accounts). Each study employed a version of the Dimensional Change Card Sort (DCCS), in which children are required first to sort cards by one pair of rules (e.g., color rules: "If red then here, if blue then there"), and then sort the same cards by another, incompatible pair of rules (e.g., shape rules). Study 1 found that although most 3- to 4-year-olds failed the standard version of this task (i.e., they perseverated on the preswitch rules during the postswitch phase), they usually performed well when they were required to use four rules (including bidimensional rules) and those rules were not in conflict (i.e., they did not require children to respond in two different ways to the same test card). These findings indicate that children's perseveration cannot be attributed in a straightforward fashion to limitations in children's memory capacity. Study 2 examined the circumstances in which children can use conflicting rules. Three experiments demonstrated effects of rule dimensionality (uni- vs. bidimensional rules) but no effects of stimulus characteristics (1 vs. 2 test cards; spatially integrated vs. separated stimuli). Taken together, these studies suggest that conflict among rules is a key determinant of difficulty, but that conflict interacts with dimensionality. Study 3 examined what types of conflict pose problems for 3- to 4-year-olds by comparing performance on standard, Partial Change, and Total Change versions of the DCCS. Results revealed effects of conflict at the level of specific rules (e.g., "If red, then there"), rather than specific stimulus configurations or dimensions per se, indicating that activation of the preswitch rules persists into the postswitch phase. Study 4 examined whether negative priming also contributes to difficulty on the DCCS. Two experiments suggested that the active selection of preswitch rules against a competing alternative results in the lasting suppression of the alternative. Taken together, the results of these studies provide the basis for a revision of the CCC theory (CCC-r) that specifies more clearly the circumstances in which children will have difficulty using rules at various levels of complexity, provides a more detailed account of how to determine the complexity of rules required in a task, takes account of both the activation and inhibition of rules as a function of experience, and highlights the importance of taking intentionality seriously in the study of executive function.
851 citations