Comparative evaluation of intranasal dexmedetomidine, intranasal midazolam, and nitrous oxide for conscious sedation of anxious children undergoing dental treatment: A randomized cross-over trial.

BACKGROUND: Pharmacological methods, specifically sedatives, have gained popularity in managing the behavior of children during dental appointments. AIM: The aim of this study was to compare 1 m/kg intranasal dexmedetomidine, 0.3 mg/kg intranasal midazolam, and nitrous oxide in evaluating the level of sedation, behavior of the child, onset of sedation, physiologic signs, and adverse effects. MATERIALS AND METHODS: In this cross-over trial, 15 children aged 6-8 years were randomized to receive intranasal atomized dexmedetomidine, intranasal atomized midazolam, and inhalation nitrous oxide at three separate visits. After administering the sedative agent, a single pulpectomy was performed during each appointment, and the outcomes were recorded. The washout period between each visit was 1 week. RESULTS: All three sedative agents were equally effective in controlling overall behavior. Dexmedetomidine showed lower sedation level scores (agitated; score 9) than the other groups. There was a statistically significant difference in the onset of sedation, with dexmedetomidine having the longest onset of 36.2 ± 9.47 min. Coughing and sneezing were predominantly observed after administration of intranasal midazolam. Oxygen saturation levels were statistically lower in the intranasal midazolam group during local anesthesia administration and post-treatment. CONCLUSION: 0.3 mg/kg intranasal midazolam is as effective as nitrous oxide sedation for controlling behavior and providing adequate sedation in pediatric dental patients. However, 1 m/kg dexmedetomidine did not provide the same level of sedation and had a significantly longer onset. 0.3 mg/kg intranasal midazolam is an effective alternative to nitrous oxide sedation in anxious children.

Maternal Urinary Fluoride and Child Neurobehavior at Age 36 Months.

Importance: Recent studies in Canadian and Mexican populations suggest an association of higher prenatal fluoride exposure with poorer neurobehavioral development, but whether this association holds for US-based populations is unknown. Objective: To examine associations of third trimester maternal urinary fluoride (MUF) with child neurobehavior at age 3 years in the US. Design, Setting, and Participants: This prospective cohort study utilized urine samples archived from 2017 to 2020 and neurobehavioral data assessed from 2020 to 2023 from the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) pregnancy cohort, which consisted of predominately Hispanic women residing in Los Angeles, California. Cohort eligibility criteria at recruitment included being 18 years of age or older, less than 30 weeks' gestation, and a fluent English or Spanish speaker. Exclusion criteria included having a disability preventing participation or provision of informed consent, being HIV positive or incarcerated, and having a multiple gestation pregnancy. There were 263 mother-child pairs who completed the 3-year study visit. In this analysis, women who reported prenatal smoking were excluded. Data analysis was conducted from October 2022 to March 2024. Exposure: Specific gravity-adjusted MUF (MUFSG), a biomarker of prenatal fluoride exposure. Main Outcomes and Measures: Neurobehavior was quantified using the Preschool Child Behavior Checklist (CBCL), which included composite scores for Total Problems, Internalizing Problems, and Externalizing Problems. CBCL composite T scores range from 28 to 100. T scores from 60 to 63 are in the borderline clinical range, whereas scores above 63 are in the clinical range. Linear and logistic regression models adjusted for covariates were conducted. Results: A total of 229 mother-child pairs (mean [SD] maternal age, 29.45 [5.67] years; 116 female children [50.7%] and 113 male children [49.3%]) who had MUFSG measured were included in the study. Median (IQR) MUFSG was 0.76 (0.51-1.19) mg/L, and 32 participants (14.0%) had a Total Problems T score in the borderline clinical or clinical range. A 1-IQR (0.68 mg/L) increase in MUFSG was associated with nearly double the odds of the Total Problems T score being in the borderline clinical or clinical range (odds ratio, 1.83; 95% CI, 1.17-2.86; P = .008), as well as with a 2.29-point increase in T score for the Internalizing Problems composite (B = 2.29; 95% CI, 0.47-4.11; P = .01) and a 2.14-point increase in T score for the Total Problems composite (B = 2.14; 95% CI, 0.29-3.98; P = .02). Conclusions and Relevance: In this prospective cohort study of mother-child pairs in Los Angeles, California, prenatal fluoride exposure was associated with increased neurobehavioral problems. These findings suggest that there may be a need to establish recommendations for limiting fluoride exposure during the prenatal period.

Investigating the relationship between prenatal alcohol exposure and children's behavioural and emotional development: analysis of the Growing Up in New Zealand study.

AIMS: To examine the relationship between prenatal alcohol exposure (PAE) and children's behavioural and emotional development in a large generalizable sample of women and their children in Aotearoa New Zealand. METHODS: Using data from the Growing Up in New Zealand longitudinal cohort, we investigated the relationship between maternal PAE and behavioural and emotional development in 8-year-old children. We explored secondary outcomes including measures of language, executive function, academic achievement, and adaptive behaviour. RESULTS: We found no significant differences in the measures of behavioural and emotional development in children 8 years old based on alcohol consumption. No significant differences in behavioural and emotional development were found based on amount of PAE and when PAE occurred, despite controlling for a range of potential confounding factors, such as neighbourhood deprivation and maternal health measures. PAE was associated with significantly higher scores for parent-rated oral language indicating better oral language. In Maori mothers, PAE was significantly associated with an increased risk of higher scores on two of the Strengths and Difficulties Questionnaire subscales. CONCLUSIONS: We did not find an association between PAE and behavioural and emotional development in children aged 8 years. PAE and behavioural and emotional development are difficult to measure accurately, and the moderating variables between them are complex. Future analyses will require larger cohorts of mothers and their children using precise measures of PAE and outcomes to enable more precise estimates of association.

The Effect of Temperament on Outcomes of Opioid and Non-Opioid Pediatric Dental Sedation.

Purpose: To assess oral sedation success using midazolam and hydroxyzine with and without meperidine, and to assess the relationship between child temperament and sedation outcomes. Methods: This study recruited children between the ages of 36 and 95 months who were randomly assigned to receive dental treatment with an oral sedation regimen of midazolam (0.5 mg/kg) and hydroxyzine (1.0 mg/kg) with or without meperidine (1.5 mg/kg). Data were collected from the treatment log and electronic health records. Parents completed the Child Behavior Questionnaire Short Form (CBQ-SF) to assess temperament. Results: The study included 37 participants. The overall treatment success rate was 54 percent. There were no significant differences in sedation outcome with age, sex, insurance status, sedation regimen, isolation method or duration of procedure. Children with high pre-operative Frankl behavioral ratings were more likely to have a successful sedation outcome (P <0.01). Children who displayed high soothability experienced higher rates of success (P =0.04), which was more pronounced in the non-opioid group (P <0.01). Conclusion: The study showed low rates of success for a relatively small sample size. There was no difference in sedation success between the opioid group and non-opioid group. However, pre-procedure behavior and temperament characteristic of sooth- ability may warrant more exploration as predictors of sedation success.

Prenatal particulate matter exposure is linked with neurobehavioural development in early life.

BACKGROUND: Early life exposure to ambient particulate matter (PM) may negatively affect neurobehavioral development in children, influencing their cognitive, emotional, and social functioning. Here, we report a study on prenatal PM2.5 exposure and neurobehavioral development focusing on different time points in the first years of life. METHODS: This study was part of the ENVIRONAGE birth cohort that follows mother-child pairs longitudinally. First, the Neonatal Behavioral Assessment Scale (NBAS) was employed on 88 newborns aged one to two months to assess their autonomic/physiological regulation, motor organisation, state organisation/regulation, and attention/social interaction. Second, our study included 393 children between the ages of four and six years, for which the Strengths and Difficulties Questionnaire (SDQ) was used to assess the children's emotional problems, hyperactivity, conduct problems, peer relationship, and prosocial behaviour. Prenatal PM2.5 exposure was determined using a high-resolution spatial-temporal method based on the maternal address. Multiple linear and multinomial logistic regression models were used to analyse the relationship between prenatal PM2.5 exposure and neurobehavioral development in newborns and children, respectively. RESULTS: A 5 µg/m³ increase in first-trimester PM2.5 concentration was associated with lower NBAS range of state cluster scores (-6.11%; 95%CI: -12.00 to -0.23%; p = 0.04) in one-to-two-month-old newborns. No other behavioural clusters nor the reflexes cluster were found to be associated with prenatal PM2.5 exposure. Furthermore, a 5 µg/m³ increment in first-trimester PM2.5 levels was linked with higher odds of a child experiencing peer problems (Odds Ratio (OR) = 3.89; 95%CI: 1.39 to 10.87; p = 0.01) at ages four to six. Additionally, a 5 µg/m³ increase in second-trimester PM2.5 concentration was linked to abnormal prosocial behaviour (OR = 0.49; 95%CI: 0.25 to 0.98; p = 0.04) at four to six years old. No associations were found between in utero PM2.5 exposure and hyperactivity or conduct problems. CONCLUSIONS: Our findings suggest that prenatal exposure to PM may impact neurobehavioural development in newborns and preschool children. We identified sensitive time windows during early-to-mid pregnancy, possibly impacting stage changes in newborns and peer problems and prosocial behaviour in children.

Organophosphorus pesticide exposure from house dust and parent-reported child behavior in Latino children from an orchard community.

BACKGROUND: Organophosphorus pesticide (OP) exposure is known to have adverse effects on the nervous system. Children from agricultural communities are at risk of exposure to these chemicals from their indoor environments that can lead to neurological and developmental problems, including changes in behavior. OBJECTIVE: The aim of this study is to evaluate whether the take-home pathway exposure is associated with behavioral and emotional problems in Latino Orchid Community children. METHOD: The study was implemented over a period of two years (2008-2010) in an orchard farming community with a total of 324 parents who had children between the ages of 5-12 years old. Mothers of the children were asked to complete the Child Behavior Checklist (CBCL) and dust from their carpets was collected. Emotional and behavioral deficits were assessed based on the CBCL and house dust was assessed for OP concentrations. In this study, correlations between OPs in house dust and CBCL subscales were estimated using linear regression models with total OP concentrations classified by tertiles. This study also facilitated the comparison between the agricultural and non-agricultural families in terms of behavioral deficits and house dust concentrations of pesticides. RESULTS: The data from the study shows that there was a positive association between the concentration of OP residues in house dust and internalizing behavior (ß=2.06, p=0.05) whereas the association with externalizing behavior was not significant after accounting for sociocultural covariates. Significant positive associations of OP residues with somatic problems (p=0.02) and thought problems (p=0.05) were also found. CONCLUSION: The data support a potential role of OP exposure in childhood development, with a specific focus on internalizing behavior. Future work focused on longitudinal studies may uncover the long-term consequences of OP exposure and behavior.

Prenatal exposure to per- and polyfluoroalkyl substances and child behavioral problems.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may adversely affect child behaviors; however, findings of epidemiologic studies are inconsistent. We examined prenatal PFAS exposure in association with child behavioral problems. METHODS: Participants were 177 mother-child pairs from MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a cohort with elevated familial likelihood of autism spectrum disorder (ASD). We quantified nine PFAS in maternal serum (1-3 samples per mother) collected from the 1st to 3rd trimesters of pregnancy. Child behavioral problems were assessed at 3 years of age using the Child Behavior Checklist (CBCL), developed to test for various behavioral problems of children. We examined associations of the CBCL scores with individual PFAS concentrations and with their mixture using negative binomial regression and weighted quantile sum regression models. RESULTS: Higher prenatal perfluorononanoate (PFNA) concentrations were associated with higher scores of externalizing problems [ß = 0.16, 95% CI (0.01, 0.32)] and aggressive behavior [ß = 0.17 (0.01, 0.32)]. Higher PFNA, perfluorooctane sulfonate (PFOS), and perfluorodecanoate (PFDA) were associated with higher scores of sleep problems [ß = 0.34 (0.15, 0.54) for PFNA, ß = 0.20 (0.02, 0.37) for PFOS, and ß = 0.19 (0.00, 0.37) for PFDA]. No significant associations observed for typically developing children, whereas PFOS, PFNA, and PFDA were associated with several behavioral problems among children diagnosed with ASD or other neurodevelopmental concerns. Exposure to a mixture of PFAS was associated with higher scores of sleep problems and aggressive behavior, mostly contributed by PFNA and PFDA. CONCLUSIONS: Our study showed that prenatal exposure to some PFAS could increase child behavioral problems at 3 years of age. However, our results should be interpreted with caution because we relied on data from a cohort with increased familial likelihood of ASD and thereby had more behavioral problems.

Effects of Yi-Gan-san on the psychiatric behavior of children and adolescents with Tourette's Syndrome: A randomized, double-blind, controlled preliminary study.

ETHNOPHARMACOLOGICAL RELEVANCE: Gilles de la Tourette's Syndrome (TS) is a childhood-onset disease with clinical features of motor and phonic tics. Yi-Gan-san (YGS) is a traditional Chinese medicine formula that can reduce aggressiveness and agitation and inhibit dopamine function. This study investigated the effects of YGS on the psychiatric behavior of children and adolescents with TS. METHODS: A double-blind, randomized, controlled preliminary study was conducted. A total of 38 patients with TS were assigned to the control group (CG, 19 patients) who received the oral administration of YGS placebo (90% starch and 10% YGS; 2.5 g thrice daily) or to a treatment group (TG, 19 patients) who received YGS for 4 weeks. The primary outcome measure was the change in Yale Global Tic Severity Scale (YGTSS) overall and subscale scores. RESULTS: The intensity score for phonic tics before oral administration of YGS, and after 2 weeks, 3 weeks and 4 weeks was not significantly different between CG and TG groups (2.94 ± 1.14 vs 2.79 ± 1.08, p = .686; 2.29 ± 1.21 vs 1.95 ± 1.08, p = .370; 2.41 ± 1.18 vs 2.05 ± 1.51, p = .435; and 2.29 ± 1.26 vs 1.84 ± 1.42, p = .323, respectively), while the intensity score for phonic tics after 1-week oral administration of YGS in the TG was 1.89 ± 1.10 lower than 3.06 ± 1.39 in the CG (p = .008). CONCLUSION: Oral administration of YGS for 1 week only reduced the intensity of phonic tics compared with oral administration of YGS placebo, suggesting that YGS can reduce their intensity for a short period, and the compliance of oral administration of YGS for 4 weeks can be accepted in children and adolescents with Tourette's Syndrome. However, because this study was preliminary, the selection of an appropriate placebo and dosage and long-term observations are crucial areas for future studies.

Prenatal docosahexaenoic acid supplementation has long-term effects on childhood behavioral and brain responses during performance on an inhibitory task.

Introduction: Offsprings from a prenatal docosahexaenoic acid (DHA) supplementation trial, in which pregnant women were assigned to placebo or 600mg DHA/day, were followed to determine the effect of prenatal DHA supplementation on the behavior and brain function at 5.5 years (n=81 placebo, n=86 supplemented).Methods: Event-related potentials (ERP) were recorded during a visual task requiring a button press (Go) to frequent target stimuli and response inhibition to the rare stimuli (No-Go). Univariate ANOVAs were used to test differences between group and sex for behavioral measures. ERP differences were tested using a three-way mixed-design multivariate analysis of variance (MANOVA).Results: There was a significant sex × group interaction for hit rate and errors of omission; there was no difference between males and females in the placebo group, but DHA males outperformed DHA females. Males overall and the placebo group made more errors requiring response inhibition; DHA females were significantly better than placebo females and DHA males. ERP P2 amplitude was larger in the DHA group. A significant N2 amplitude condition effect was observed in females and DHA group males, but not in placebo group males.Discussion: Prenatal DHA supplementation improved inhibitory performance overall, especially for females in the DHA group, possibly accounting for their conservative behavior during Go trials. Development of brain regions responsible for visual processing may be sensitive to maternal DHA status, evidenced by greater P2 amplitude. Males may benefit more from maternal DHA supplementation, indicated by the N2 condition effect seen only in males in the DHA group.

The Influence of Prenatal DHA Supplementation on Individual Domains of Behavioral Functioning in School-Aged Children: Follow-Up of a Randomized Controlled Trial.

Docosahexaenoic acid (DHA) accumulates in the fetal brain during pregnancy and is thought to have a role in supporting neurodevelopment. We conducted a multicenter, double-blind, randomized controlled trial in women with a singleton pregnancy who were <21 weeks' gestation at trial entry. Women were provided with 800 mg DHA/day or a placebo supplement from trial entry until birth. When children reached seven years of age, we invited parents to complete the Strengths and Difficulties Questionnaire (SDQ), the Behavior Rating Inventory of Executive Function (BRIEF), and the Conners 3rd Edition Attention-Deficit Hyperactivity Disorder (ADHD) Index to assess child behavior and behavioral manifestations of executive dysfunction. There were 543 parent-child pairs (85% of those eligible) that participated in the follow-up. Scores were worse in the DHA group than the placebo group for the BRIEF Global Executive, Behavioral Regulation and Metacognition Indexes, and the Shift, Inhibit, Monitor, Working Memory, and Organization of Materials scales, as well as for the Conners 3 ADHD index, and the SDQ Total Difficulties score, Hyperactivity/Inattention score, and Peer Relationship Problems score. In this healthy, largely term-born sample of children, prenatal DHA supplementation conferred no advantage to childhood behavior, and instead appeared to have an adverse effect on behavioral functioning, as assessed by standardized parental report scales.

Prenatal exposure to opioids: Associations between the caregiving environment and externalizing behaviors.

Maternal opioid use during pregnancy is a rapidly growing public health crisis and is associated with a range of adverse developmental outcomes including externalizing behaviors among exposed children. Recent work has highlighted the role of indirect pathways from prenatal opioid exposure to behavioral outcomes through aspects of the caregiving environment, including parenting. This review highlights maternal sensitivity and related aspects of the caregiving environment that may impact the development of externalizing behaviors among children with a history of prenatal exposure to opioids. We conclude by providing suggestions for future directions in research examining development among children with prenatal opioid exposure.

The effects of the exposure to neurotoxic elements on Italian schoolchildren behavior.

Neurodevelopmental disorders are constantly increasing on a global scale. Some elements like heavy metals are known to be neurotoxic. In this cross-sectional study we assessed the neurobehavioral effect of the exposure to trace elements including lead, mercury, cadmium, manganese, arsenic and selenium and their interactions among 299 schoolchildren residing in the heavily polluted Taranto area in Italy. Whole blood, urine and hair were collected for metal analyses, while the Child Behavior Checklist and the Social Responsiveness Scale, administered to the main teacher and the mothers were considered to identify behavioral problems in children. Blood lead mainly influenced social problems, aggressive behavior, externalizing and total problems. Urinary arsenic showed an impact on anxiety and depression, somatic problems, attention problems and rule breaking behavior. A significant interaction between lead and arsenic was observed, with a synergistic effect of the two metals increasing the risk of attention problems, aggressive behavior, externalizing problems and total problems. Overall, we were able to test that higher blood lead, urinary arsenic concentrations and their interaction increase the risk of neurobehavioral problems. This is in line with the U.S. Environmental Protection Agency's priority list of hazardous substances where arsenic and lead are ranked as first and second respectively.

Association of blood lead levels with neurobehavior and BDNF expression in school going children.

BACKGROUND: Childhood Lead (Pb) toxicity has been an ongoing concern for decades; however, its underlying pathogenesis remains unclear. Although its prevalence has come down in developed countries (USA, Europe); it is relatively high in low to middle-income countries of South-East Asia. The current study aimed to evaluate the association of blood lead levels (BLLs) with neurobehavioral alterations and changes in Brain-Derived Neurotropic Factor (BDNF) expression in Indian school children. METHODOLOGY: School going children in age group of 9-15 years (N = 72) were included in the study. Neurobehavioral changes were assessed using Childhood Psychopathological Measurement Schedule (CPMS) and BLL were measured by Graphite Furnace Atomic Absorption Spectrophotometry (GFAAS). BDNF mRNA expression and serum BDNF levels were assessed by Real-Time PCR and ELISA, respectively. RESULTS: Median BLL was 4.95 µg/dL (IQR = 4.47), very close to the recommended toxic cut off levels (<5 µg/dL). BLLs had a direct correlation with both CPMS scores and BDNF expression. Depression was found to be significantly higher in boys than in girls with high BLLs. BDNF mRNA expression and serum BDNF levels were higher among children with high BLL, although not to significant levels. CONCLUSION: We report a significant association of neurobehavioral changes with the prevalence of high Pb levels in Indian children. Additionally significant correlation of BDNF with BLL in these children suggests a causal role of BDNF in Pb induced neurological damage.

Short-term outcomes of pubertal suppression in a selected cohort of 12 to 15 year old young people with persistent gender dysphoria in the UK.

BACKGROUND: In adolescents with severe and persistent gender dysphoria (GD), gonadotropin releasing hormone analogues (GnRHa) are used from early/middle puberty with the aim of delaying irreversible and unwanted pubertal body changes. Evidence of outcomes of pubertal suppression in GD is limited. METHODS: We undertook an uncontrolled prospective observational study of GnRHa as monotherapy in 44 12-15 year olds with persistent and severe GD. Prespecified analyses were limited to key outcomes: bone mineral content (BMC) and bone mineral density (BMD); Child Behaviour CheckList (CBCL) total t-score; Youth Self-Report (YSR) total t-score; CBCL and YSR self-harm indices; at 12, 24 and 36 months. Semistructured interviews were conducted on GnRHa. RESULTS: 44 patients had data at 12 months follow-up, 24 at 24 months and 14 at 36 months. All had normal karyotype and endocrinology consistent with birth-registered sex. All achieved suppression of gonadotropins by 6 months. At the end of the study one ceased GnRHa and 43 (98%) elected to start cross-sex hormones. There was no change from baseline in spine BMD at 12 months nor in hip BMD at 24 and 36 months, but at 24 months lumbar spine BMC and BMD were higher than at baseline (BMC +6.0 (95% CI: 4.0, 7.9); BMD +0.05 (0.03, 0.07)). There were no changes from baseline to 12 or 24 months in CBCL or YSR total t-scores or for CBCL or YSR self-harm indices, nor for CBCL total t-score or self-harm index at 36 months. Most participants reported positive or a mixture of positive and negative life changes on GnRHa. Anticipated adverse events were common. CONCLUSIONS: Overall patient experience of changes on GnRHa treatment was positive. We identified no changes in psychological function. Changes in BMD were consistent with suppression of growth. Larger and longer-term prospective studies using a range of designs are needed to more fully quantify the benefits and harms of pubertal suppression in GD.

The Influence of Omega-3 Long-Chain Polyunsaturated Fatty Acid, Docosahexaenoic Acid, on Child Behavioral Functioning: A Review of Randomized Controlled Trials of DHA Supplementation in Pregnancy, the Neonatal Period and Infancy.

This is a review of randomized controlled trials using docosahexaenoic acid (DHA) interventions in the first 1000 days of life with assessments of behavioral functioning in childhood. Electronic databases were searched for trials with a DHA intervention (compared with a placebo group that received no or less DHA) at any time to either women or infants during the first 1000 days, with a subsequent assessment of child behavior. There were 25 trials involving 10,320 mother-child pairs, and 71 assessments of behavior in 6867 of the children (66.5% of those originally enrolled). From the 71 assessments administered, there were 401 comparisons between a DHA group and a control group, with most reporting a null effect. There were no findings of a positive effect of DHA, and 23 instances where the DHA group had worse scores compared with the control group. There was limited evidence that DHA supplementation had any effect on behavioral development, although two of the largest trials with behavioral measures detected adverse effects. Future trials, and future follow-ups of existing trials, should make an effort to evaluate the effect of DHA intervention on behavioral functioning.

Prenatal Exposure to General Anesthesia and Childhood Behavioral Deficit.

BACKGROUND: Exposure to surgery and anesthesia in early childhood has been found to be associated with an increased risk of behavioral deficits. While the US Food and Drug Administration (FDA) has warned against prenatal exposure to anesthetic drugs, little clinical evidence exists to support this recommendation. This study evaluates the association between prenatal exposure to general anesthesia due to maternal procedures during pregnancy and neuropsychological and behavioral outcome scores at age 10. METHODS: This is an observational cohort study of children born in Perth, Western Australia, with 2 generations of participants contributing data to the Raine Study. In the Raine Study, the first generation (Gen1) are mothers enrolled during pregnancy, and the second generation (Gen2) are the children born to these mothers from 1989 to 1992 with neuropsychological and behavioral tests at age 10 (n=2024). In the primary analysis, 6 neuropsychological and behavioral tests were evaluated at age 10: Raven's Colored Progressive Matrices (CPM), McCarron Assessment of Neuromuscular Development (MAND), Peabody Picture Vocabulary Test (PPVT), Symbol Digit Modality Test (SDMT) with written and oral scores, Clinical Evaluation of Language Fundamentals (CELF) with Expressive, Receptive, and Total language scores, and Child Behavior Checklist (CBCL) with Internalizing, Externalizing, and Total behavior scores. Outcome scores of children prenatally exposed to general anesthesia were compared to children without prenatal exposure using multivariable linear regression models adjusting for demographic and clinical covariates (sex, race, income, and maternal education, alcohol or tobacco use, and clinical diagnoses: diabetes, epilepsy, hypertension, psychiatric disorders, or thyroid dysfunction). Bonferroni adjustment was used for the 6 independent tests in the primary analysis, so a corrected P value <.0083 (P = .05 divided by 6 tests, or a 99.17% confidence interval [CI]) was required for statistical significance. RESULTS: Among 2024 children with available outcome scores, 22 (1.1%) were prenatally exposed to general anesthesia. Prenatally exposed children had higher CBCL Externalizing behavioral scores (score difference of 6.1 [99.17% CI, 0.2-12.0]; P = .006) than unexposed children. Of 6 tests including 11 scores and subscores, only CBCL Externalizing behavioral scores remained significant after multiple comparisons adjustment with no significant differences found in any other score. CONCLUSIONS: Prenatal exposure to general anesthetics is associated with increased externalizing behavioral problems in childhood. However, given the limitations of this study and that avoiding necessary surgery during pregnancy can have significant detrimental effects on the mother and the child, further studies are needed before changes to clinical practice are made.

Behavioral consequences at 5 y of neonatal iron deficiency in a low-risk maternal-infant cohort.

BACKGROUND: Iron is critical to the developing brain, but fetal iron accretion is compromised by several maternal and pregnancy-related factors. Little consideration has been given to the long-term neurologic consequences of neonatal iron deficiency, especially in generally healthy, low-risk populations. OBJECTIVE: We aimed to investigate the association between neonatal iron deficiency and neurologic development at 2 and 5 y of age. DESIGN: We measured umbilical cord serum ferritin concentrations in the prospective maternal-infant Cork BASELINE (Babies after SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints) Birth Cohort. Lifestyle and clinical data were collected from 15 weeks of gestation to 5 y of age. Standardized neurologic assessments were performed at 2 y [Bayley Scales of Infant Development/Child Behavior Checklist (CBCL)] and 5 y (Kaufman Brief Intelligence Test/CBCL). RESULTS: Among 697 maternal-infant pairs, median (IQR) cord ferritin concentrations were 200.9 (139.0, 265.8) µg/L; 8% had neonatal iron deficiency (ferritin <76 µg/L). Using fully adjusted models, there was no association between neonatal iron deficiency and cognitive or behavioral outcomes at 2 or 5 y. We conducted an a priori sensitivity analysis in 306 high-risk children, selected using known risk factors for neonatal iron deficiency (smoking/obesity/cesarean section delivery/small-for-gestational age birth). In this high-risk subgroup, children with iron deficiency at birth (12%) had similar cognitive outcomes, but the behavioral assessments showed higher internalizing [9.0 (5.3, 12.0) compared with 5.0 (3.0, 10.0), P = 0.006; adjusted estimate (95% CI): 2.8 (0.5, 5.1), P = 0.015] and total [24.5 (15.3, 40.8) compared with 16.0 (10.0, 30.0), P = 0.009; adjusted estimate (95% CI): 6.6 (0.1, 13.1), P = 0.047] problem behavior scores at 5 y compared with those born iron sufficient. CONCLUSIONS: We have demonstrated lasting behavioral consequences of neonatal iron deficiency in high-risk children from our generally healthy, low-risk maternal-infant cohort. Although larger investigations are warranted, this study provides strong association data to suggest that interventions and strategies targeting the fetal and neonatal period should be prioritized for the prevention of iron deficiency and associated neurologic consequences.

Behavioral Problems at Age 11 Years After Prenatal and Postnatal Exposure to Acetaminophen: Parent-Reported and Self-Reported Outcomes.

Several studies have reported associations between prenatal acetaminophen exposure and behavioral outcomes in young children. We aimed to evaluate the associations of prenatal and postnatal exposures to acetaminophen with behavioral problems in children at age 11 years, using behavioral measures reported by parents and children. We studied 40,934 mother-child pairs from the Danish National Birth Cohort enrolled during 1996-2002. Parent-reported and child-reported Strengths and Difficulties Questionnaire (SDQ) responses were collected during the 11-year follow-up. We estimated risk ratios for behavioral problems including total difficulties as well as internalizing or externalizing behaviors following prenatal (during pregnancy) or postnatal (within the first 18 months after birth) acetaminophen exposure. Parent-reported and child-reported SDQ scores were moderately correlated; higher for externalizing (r = 0.59) than internalizing (r = 0.49) behaviors. Prenatal acetaminophen exposure was associated with 10%-40% higher risks for total difficulties and internalizing and externalizing problems based on parent- or child-reported SDQ, with the association being stronger for greater cumulative weeks of acetaminophen use. Postnatal exposure was associated with 16%-19% higher risks for parent-reported internalizing behaviors, but the associations were weak or null for child-reported scores except for prosocial behavior. Our study corroborates published associations between prenatal exposures to acetaminophen and behavioral problems and extends the literature to early adolescence.

Association Between Behavioral and Learning Outcomes and Single Exposures to Procedures Requiring General Anesthesia Before Age 3: Secondary Analysis of Data From Olmsted County, MN.

BACKGROUND: Two prior population-based (children born in Olmsted County, MN), retrospective cohort studies both found that multiple exposures to anesthesia before age 3 were associated with a significant increase in the frequency of attention-deficit hyperactivity disorder (ADHD) and learning disabilities (LD) later in life. The primary purpose of this secondary analysis of these data was to test the hypothesis that a single exposure to anesthesia before age 3 was associated with an increased risk of ADHD. We also examined the association of single exposures with LD and the need for individualized educational plans as secondary outcomes. METHODS: This analysis includes 5339 children who were unexposed to general anesthesia before age 3 (4876 born from 1976 to 1982 and 463 born from 1996 to 2000), and 1054 children who had a single exposure to anesthesia before age 3 (481 born from 1976 to 1982 and 573 born from 1996 to 2000). The primary outcome of interest was ADHD. Secondary outcomes included LD (reading, mathematics, and written language) and the need for individualized educational programs (speech/language and emotion/behavior). To compare the incidence of each outcome between those who were unexposed and singly exposed to anesthesia before the age of 3 years, an inverse probability of treatment weighted proportional hazards model was used. RESULTS: For children not exposed to anesthesia, the estimated cumulative frequency (95% confidence interval [CI]) of ADHD at age 18 was 7.3% (95% CI, 6.5-8.1) and 13.0% (95% CI, 10.1-16.8) for the 1976-1982 and 1996-2000 cohorts, respectively. For children exposed to a single anesthetic before age 3, the cumulative frequency of ADHD was 8.1% (95% CI, 5.3-12.4) and 17.6% (95% CI, 14.0-21.9) for the 1976-1982 and 1996-2000 cohorts, respectively. In weighted analyses, single exposures were not significantly associated with an increased frequency of ADHD (hazard ratio [HR], 1.21; 95% CI, 0.91-1.60; P = .184). Single exposures were also not associated with an increased frequency of any LD (HR, 0.98; 95% CI, 0.78-1.23), or the need for individualized education plans. CONCLUSIONS: This analysis did not find evidence that single exposures to procedures requiring general anesthesia, before age 3, are associated with an increased risk of developing ADHD, LD, or the need for individualized educational plans in later life.