Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies.

BACKGROUND: Fluoride may be a developmental neurotoxicant at elevated exposures. We merged new data from a prospective Odense Child Cohort (OCC) with results from two previous birth cohort studies from Mexico and Canada to characterize the dose-effect relationship in greater detail. METHODS: The OCC contributed 837 mother-child pairs to the total of >1500. We measured creatinine-adjusted urine-fluoride concentrations in maternal urine samples obtained during late pregnancy. Child IQ was determined at age 7 years using an abbreviated version of the Wechsler Intelligence Scales for Children. Findings from the three cohorts were used to calculate the joint benchmark concentration (BMC) and the lower confidence limit (BMCL) after adjustment for covariables. RESULTS: In the OCC, urine-fluoride concentrations varied between 0.08 and 3.04 mg/l (median 0.52 mg/l) but were not significantly associated with full-scale IQ at age 7 years (ß = 0.08; 95% confidence interval -1.14 to 1.30 for a doubling in exposure). No difference was apparent between boys and girls. In the OCC, the BMC was 0.92 mg/l, with a BMCL of 0.30 mg/l. The joint analysis of all three cohorts showed a statistically significant association between urine-fluoride and IQ, with a BMC of 0.45 mg/l (BMCL, 0.28 mg/l), slightly higher than the BMC previously reported for the two North American cohorts alone. CONCLUSIONS: As the BMCL reflects an approximate threshold for developmental neurotoxicity, the results suggest that pregnant women and children may need protection against fluoride toxicity.

Sex difference of pre- and post-natal exposure to six developmental neurotoxicants on intellectual abilities: a systematic review and meta-analysis of human studies.

BACKGROUND: Early life exposure to lead, mercury, polychlorinated biphenyls (PCBs), polybromide diphenyl ethers (PBDEs), organophosphate pesticides (OPPs), and phthalates have been associated with lowered IQ in children. In some studies, these neurotoxicants impact males and females differently. We aimed to examine the sex-specific effects of exposure to developmental neurotoxicants on intelligence (IQ) in a systematic review and meta-analysis. METHOD: We screened abstracts published in PsychINFO and PubMed before December 31st, 2021, for empirical studies of six neurotoxicants (lead, mercury, PCBs, PBDEs, OPPs, and phthalates) that (1) used an individualized biomarker; (2) measured exposure during the prenatal period or before age six; and (3) provided effect estimates on general, nonverbal, and/or verbal IQ by sex. We assessed each study for risk of bias and evaluated the certainty of the evidence using Navigation Guide. We performed separate random effect meta-analyses by sex and timing of exposure with subgroup analyses by neurotoxicant. RESULTS: Fifty-one studies were included in the systematic review and 20 in the meta-analysis. Prenatal exposure to developmental neurotoxicants was associated with decreased general and nonverbal IQ in males, especially for lead. No significant effects were found for verbal IQ, or postnatal lead exposure and general IQ. Due to the limited number of studies, we were unable to analyze postnatal effects of any of the other neurotoxicants. CONCLUSION: During fetal development, males may be more vulnerable than females to general and nonverbal intellectual deficits from neurotoxic exposures, especially from lead. More research is needed to examine the nuanced sex-specific effects found for postnatal exposure to toxic chemicals.

Domain-specific effects of prenatal fluoride exposure on child IQ at 4, 5, and 6-12 years in the ELEMENT cohort.

OBJECTIVE: Prenatal exposure to fluoride has been associated with adverse neurodevelopmental outcomes. However, the neuropsychological profile of fluoride's developmental neurotoxicity at low levels and the stability of this relationship across childhood has not been characterized. We investigated the longitudinal and domain specific effect of prenatal fluoride exposure on IQ among children ages 4, 5, and 6-12 years in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort. METHODS: We measured the average of maternal urinary fluoride at each trimester of pregnancy adjusted for creatinine (MUFCRE). Children were administered the McCarthy Scales of Children's Abilities at ages 4 (N = 386) and 5 (N = 308), and the Wechsler Abbreviated Scale of Intelligence at age 6-12 (N = 278). We used generalized estimating equation (GEE) models to estimate the population averaged effect of MUFCRE concentration on longitudinal General Cognitive Index (GCI)/Full-Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ) scores (N = 348). We tested for possible interactions between MUFCRE and child sex as well as for MUFCRE and time point on children's IQ. All models controlled for relevant available covariates. RESULTS: The mean/median MUFCRE concentration was 0.90/0.83 mg/L (SD = 0.39; IQR, 0.64-1.11 mg/L). A 0.5 mg/L increase in MUFCRE predicted an average 2.12-point decrease in GCI/FSIQ (95% CI: -3.49, -0.75) and 2.63-point decrease in PIQ (95% CI: -3.87, -1.40). MUFCRE was marginally associated with VIQ across time (B = -1.29, 95% CI: -2.60, 0.01). No interactions between MUFCRE and child sex or MUFCRE and time were observed. CONCLUSION: The negative association between prenatal fluoride exposure and longitudinal IQ was driven by decrements in non-verbal intelligence (i.e. PIQ), suggesting that visual-spatial and perceptual reasoning abilities may be more impacted by prenatal fluoride exposure as compared to verbal abilities.

A Benchmark Dose Analysis for Maternal Pregnancy Urine-Fluoride and IQ in Children.

As a guide to establishing a safe exposure level for fluoride exposure in pregnancy, we applied benchmark dose modeling to data from two prospective birth cohort studies. We included mother-child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Maternal urinary fluoride concentrations (U-F, in mg/L, creatinine-adjusted) were measured in urine samples obtained during pregnancy. Children were assessed for intelligence quotient (IQ) at age 4 (n = 211) and between six and 12 years (n = 287) in the ELEMENT cohort, and three to four years (n = 407) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to assess the association of maternal U-F concentrations with children's IQ measures. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) and benchmark concentration levels (BMCLs). No deviation from linearity was detected in the dose-response relationships, but boys showed lower BMC values than girls. Using a linear slope for the joint cohort data, the BMC for maternal U-F associated with a 1-point decrease in IQ scores was 0.31 mg/L (BMCL, 0.19 mg/L) for the youngest boys and girls in the two cohorts, and 0.33 mg/L (BMCL, 0.20 mg/L) for the MIREC cohort and the older ELEMENT children. Thus, the joint data show a BMCL in terms of the adjusted U-F concentrations in the pregnant women of approximately 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in pregnant women.

Controversy: The evolving science of fluoride: when new evidence doesn't conform with existing beliefs.

Over the past 75 years, health authorities have declared that community water fluoridation-a practice that reaches over 400 million worldwide-is safe. Yet, studies conducted in North America examining the safety of fluoride exposure in pregnancy were nonexistent. When a Canadian study reported that higher fluoride exposure in pregnant women was associated with lower IQ scores in young children, critics attacked the methodology of the study and discounted the significance of the results. Health authorities continued to conclude that fluoride is unequivocally safe, despite four well-conducted studies over the last 3 years consistently linking fluoride exposure in pregnancy with adverse neurodevelopmental effects in offspring. We describe the challenges of conducting fluoride research and the overt cognitive biases we have witnessed in the polarized fluoride debate. The tendency to ignore new evidence that does not conform to widespread beliefs impedes the response to early warnings about fluoride as a potential developmental neurotoxin. Evolving evidence should inspire scientists and health authorities to re-evaluate claims about the safety of fluoride, especially for the fetus and infant for whom there is no benefit.

Critical windows of fluoride neurotoxicity in Canadian children.

BACKGROUND: Fluoride has been associated with IQ deficits during early brain development, but the period in which children are most sensitive is unknown. OBJECTIVE: We assessed effects of fluoride on IQ scores across prenatal and postnatal exposure windows. METHODS: We used repeated exposures from 596 mother-child pairs in the Maternal-Infant Research on Environmental Chemicals pregnancy and birth cohort. Fluoride was measured in urine (mg/L) collected from women during pregnancy and in their children between 1.9 and 4.4 years; urinary fluoride was adjusted for specific gravity. We estimated infant fluoride exposure (mg/day) using water fluoride concentration and duration of formula-feeding over the first year of life. Intelligence was assessed at 3-4 years using the Wechsler Preschool and Primary Scale of Intelligence-III. We used generalized estimating equations to examine the associations between fluoride exposures and IQ, adjusting for covariates. We report results based on standardized exposures given their varying units of measurement. RESULTS: The association between fluoride and performance IQ (PIQ) significantly differed across prenatal, infancy, and childhood exposure windows collapsing across child sex (p = .001). The strongest association between fluoride and PIQ was during the prenatal window, B = -2.36, 95% CI: -3.63, -1.08; the association was also significant during infancy, B = -2.11, 95% CI: -3.45, -0.76, but weaker in childhood, B = -1.51, 95% CI: -2.90, -0.12. Within sex, the association between fluoride and PIQ significantly differed across the three exposure windows (boys: p = .01; girls: p = .01); among boys, the strongest association was during the prenatal window, B = -3.01, 95% CI: -4.60, -1.42, whereas among girls, the strongest association was during infancy, B = -2.71, 95% CI: -4.59, -0.83. Full-scale IQ estimates were weaker than PIQ estimates for every window. Fluoride was not significantly associated with Verbal IQ across any exposure window. CONCLUSION: Associations between fluoride exposure and PIQ differed based on timing of exposure. The prenatal window may be critical for boys, whereas infancy may be a critical window for girls.

Fluoride exposure and duration and quality of sleep in a Canadian population-based sample.

BACKGROUND: Fluoride from dietary and environmental sources may concentrate in calcium-containing regions of the body such as the pineal gland. The pineal gland synthesizes melatonin, a hormone that regulates the sleep-wake cycle. We examined associations between fluoride exposure and sleep outcomes among older adolescents and adults in Canada. METHODS: We used population-based data from Cycle 3 (2012-2013) of the Canadian Health Measures Survey. Participants were aged 16 to 79 years and 32% lived in communities supplied with fluoridated municipal water. Urinary fluoride concentrations were measured in spot samples and adjusted for specific gravity (UFSG; n = 1303) and water fluoride concentrations were measured in tap water samples among those who reported drinking tap water (n = 1016). We used multinomial and ordered logistic regression analyses (using both unweighted and survey-weighted data) to examine associations of fluoride exposure with self-reported sleep outcomes, including sleep duration, frequency of sleep problems, and daytime sleepiness. Covariates included age, sex, ethnicity, body mass index, chronic health conditions, and household income. RESULTS: Median (IQR) UFSG concentration was 0.67 (0.63) mg/L. Median (IQR) water fluoride concentration was 0.58 (0.27) mg/L among participants living in communities supplied with fluoridated municipal water and 0.01 (0.06) mg/L among those living in non-fluoridated communities. A 0.5 mg/L higher water fluoride level was associated with 34% higher relative risk of reporting sleeping less than the recommended duration for age [unweighted: RRR = 1.34, 95% CI: 1.03, 1.73; p = .026]; the relative risk was higher, though less precise, using survey-weighted data [RRR = 1.96, 95% CI: 0.99, 3.87; p = .05]. UFSG was not significantly associated with sleep duration. Water fluoride and UFSG concentration were not significantly associated with frequency of sleep problems or daytime sleepiness. CONCLUSIONS: Fluoride exposure may contribute to sleeping less than the recommended duration among older adolescents and adults in Canada.

Detection and clinical correlation of leukocortical lesions in pediatric-onset multiple sclerosis on multi-contrast MRI.

OBJECTIVE: To determine the frequency of cortical lesions (CLs) in patients with pediatric-onset multiple sclerosis (POMS) using multi-contrast magnetic resonance imaging (MRI), and the relationship between frontal CL load and upper limb dexterity assessed with the Nine-Hole Peg Test (9-HPT). METHODS: Participants completed the 9-HPT and were imaged on a 3T MRI scanner to collect T1-weighted three-dimensional (3D) magnetization prepared rapid gradient echo (MPRAGE), proton density-weighted, T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. CLs were manually segmented using all MRI contrasts. RESULTS: We enrolled 24 participants with POMS (mean (standard deviation) age at first symptom: 13.3 (±2.7) years; mean age at scan: 18.8 (±3) years; mean disease duration of 5 (±3.2) years). A total of 391 CLs (mean, 16.3 ± 27.2; median, 7) were identified in 19 of 24 POMS patients (79%). The total number of CLs was positively associated with white matter lesion volume ( p = 0.04) but not with thalamic volume, age at the time of the scan, or disease duration. The number of frontal CLs was associated with slower performance on the 9-HPT ( p = 0.05). CONCLUSION: Multi-contrast 3T MRI led to a high rate of CL detection, demonstrating that cortical pathology occurs even in pediatric-onset disease. Frontal lobe CL count was associated with reduced manual dexterity, indicating that these CLs are clinically relevant.

Enhanced Recruitment During Executive Control Processing in Cognitively Preserved Patients With Pediatric-Onset MS.

OBJECTIVES: Youth and young adults with pediatric-onset multiple sclerosis (MS) are vulnerable to executive dysfunction; however, some patients do not demonstrate functional deficits despite showing abnormalities on structural magnetic resonance imaging (MRI). Cognitively intact adults with MS have shown enhanced activation patterns relative to healthy controls on working memory tasks. We aim to evaluate whether cognitively preserved pediatric-onset MS patients engage compensatory recruitment strategies to facilitate age-normative performance on a task of working memory. METHODS: Twenty cognitively preserved patients (mean age=18.7±2.7 years; 15 female) and 20 age- and sex-matched controls (mean age=18.5±2.9 years; 15 female) underwent neuropsychological testing and 3.0 Tesla MRI, including structural and functional acquisitions. Patterns of activation during the Alphaspan task, a working memory paradigm with two levels of executive control demand, were examined via whole-brain and region of interest (ROI) analyses. RESULTS: Across all participants, lower accuracy and greater activation of regions implicated in working memory were observed during the high demand condition. MS patients demonstrated 0.21 s longer response time than controls. ROI analyses revealed enhanced activation for pediatric-onset MS patients relative to controls in the right middle frontal, left paracingulate, right supramarginal, and left superior parietal gyri during the low executive demand condition, over and above differences in response time. MS patients also demonstrated heightened activation in the right supramarginal gyrus in the high executive demand condition. CONCLUSIONS: Our findings suggest that pediatric-onset MS patients may engage compensatory recruitment strategies during working memory processing. (JINS, 2019, 25, 432-442).

A feasibility study of working memory training for individuals with paediatric-onset multiple sclerosis.

Objective: To investigate the feasibility and experiences of paediatric-onset multiple sclerosis (MS) patients completing a working memory training programme. Methods: Nine paediatric-onset MS patients (mean age 19.3 ± 4.1 years) identified as having attention and/or working memory difficulties underwent a five-week (five days/week) internet-based working memory training programme (Cogmed™); weekly coaching was provided. Measures of adherence and tolerance were used to establish the feasibility of implementing computerised cognitive training. Qualitative experiences reported by the patients were analysed and factors that may modulate the effects of training were explored. Results: Six of the nine enrolled patients completed the programme within the recommended time, and all individuals, with the exception of one, were considered to tolerate the training well. Eight of the nine participants acknowledged that training was helpful in one or more ways. All but one participant reported improvements in working memory, although evidence for improvement on objective neuropsychological testing was limited. Lower normalised brain volume emerged as a potentially important variable in predicting extent of improvement on the training programme. Conclusion: Selected paediatric-onset MS patients can tolerate and complete an intensive cognitive rehabilitation programme. Future investigation of moderators of training effects and the stability of the findings over time is needed.

Physical Activity and Its Correlates in Youth with Multiple Sclerosis.

OBJECTIVES: To investigate physical activity levels in youth with multiple sclerosis and monophasic acquired demyelinating syndromes ([mono-ADS], ie, children without relapsing disease) compared with healthy controls and to determine factors that contribute to engagement in physical activity. We hypothesized that greater physical activity goal setting and physical activity self-efficacy would be associated with greater levels of vigorous physical activity in youth with multiple sclerosis. STUDY DESIGN: A total of 68 consecutive patients (27 multiple sclerosis, 41 mono-ADS) and 37 healthy controls completed fatigue, depression, Physical Activity Self-Efficacy Scale, perceived disability, Exercise Goal-Setting scale, and physical activity questionnaires, and wore an accelerometer for 7 days. All patients had no ambulatory limitations (Expanded Disability Status Scale, scores all <4). RESULTS: Youth with multiple sclerosis engaged in fewer minutes per day of vigorous (P = .009) and moderate and vigorous physical activity (P = .048) than did patients with mono-ADS and healthy controls. A lower proportion of the group with multiple sclerosis (63%) reported participating in any strenuous physical activity than the mono-ADS (85%) and healthy control (89%) groups (P = .020). When we adjusted for age and sex, the Physical Activity Self-Efficacy Scale and Exercise Goal-Setting scale were associated positively with vigorous physical activity in the group with multiple sclerosis. Fatigue and depression did not predict physical activity or accelerometry metrics. CONCLUSIONS: Youth with multiple sclerosis participate in less physical activity than their counterparts with mono-ADS and healthy controls. Physical activity self-efficacy and exercise goal setting serve as potentially modifiable correlates of physical activity, and are measures suited to future interventions aimed to increase physical activity in youth with multiple sclerosis.

Contribution of the cerebellum to cognitive performance in children and adolescents with multiple sclerosis.

BACKGROUND: Posterior fossa lesions are common in pediatric-onset multiple sclerosis (MS), which is of concern, given the known role of the cerebellum in cognition. OBJECTIVES: To investigate the relationship between cerebellar pathology and cognitive function in youth with pediatric-onset MS. METHODS: Twenty-eight pediatric-onset relapsing-remitting MS patients (21 girls; mean age 16.2 years; mean disease duration 4.3 years, median Expanded Disability Status Scale 1.25) were compared to 33 age- and sex-matched healthy controls. Participants underwent structural magnetic resonance imaging (MRI) and neuropsychological evaluation to assess intelligence, attention, processing speed, language, visuo-motor integration, and fine-motor dexterity. Associations between cognitive outcomes and cerebellar volume independent of cerebral volume were examined. RESULTS: Cognitive and motor performance of the MS group was reduced relative to controls (all p<0.003). While cerebellar volumes did not differ between groups, cerebellar posterior lobe volume and infratentorial lesion volume accounted for extra variance on measures of information processing (R(2)=0.43; p=0.02) and vocabulary (R(2)=0.56; p=0.04) in patients (controlling for cerebral volume and sex), but not in controls. CONCLUSION: Smaller cerebellar posterior lobe volume, a known region for cognitive processing, and increased lesion burden in the posterior fossa adversely impact cognitive function, an important functional consequence of MS onset during childhood.

Altered resting-state functional connectivity in cognitively preserved pediatric-onset MS patients and relationship to structural damage and cognitive performance.

OBJECTIVE: To evaluate resting-state functional connectivity (FC) and relationship to brain volumes and cognition in a sample of cognitively preserved pediatric-onset multiple sclerosis (MS) patients. METHODS: Sixteen cognitively intact pediatric-onset MS patients and 15 healthy age- and sex-matched controls underwent cognitive testing and 3T anatomical and functional MRI. Resting-state FC patterns were examined using region-of-interest-based timeseries correlations. RESULTS: Compared to controls, pediatric-onset MS patients demonstrated higher FC of the precuneus, particularly with the anterior cingulate cortex (z=4.21, p<.001), frontal medial cortex (z=3.48, p<.001), and cerebellum (z=3.72, p<.001). Greater T2 lesion volume and lower normalized thalamic volume were associated with reduced FC of the thalamus, especially for FC with the right superior occipital region (t=-2.87, p=.0123 and t=2.27, p=.04 respectively). FC of the left frontal medial cortex was negatively correlated with composite cognitive z-score in the pediatric-onset MS group (p<.05). CONCLUSIONS: Greater resting-state FC between posterior and anterior brain regions is present in pediatric-onset MS. With greater disease-related structural pathology, there is a disruption of thalamo-cortical FC. In the absence of actual cognitive impairment, heightened FC of the frontal medial cortex was associated with lower cognitive performance, suggesting that greater functional resources are recruited during resting-state in patients with reduced cognitive efficiency.

Cognitive and Behavioral Functioning in Childhood Acquired Demyelinating Syndromes.

OBJECTIVES: The aim of this study was to describe cognitive, academic, and psychosocial outcomes after an incident demyelinating event (acquired demyelinating syndromes, ADS) in childhood and to investigate the contribution of brain lesions and confirmed MS diagnosis on outcome. METHODS: Thirty-six patients with ADS (mean age=12.2 years, SD=2.7, range: 7-16 years) underwent brain MRI scans at presentation and at 6-months follow-up. T2-weighted lesions on MRI were assessed using a binary classification. At 6-months follow-up, patients underwent neuropsychological evaluation and were compared with 42 healthy controls. RESULTS: Cognitive, academic, and behavioral outcomes did not differ between the patients with ADS and controls. Three of 36 patients (8.3%) were identified with cognitive impairment, as determined by performance falling ≤1.5 SD below normative values on more than four independent tests in the battery. Poor performance on a visuomotor integration task was most common, observed among 6/32 patients, but this did not differ significantly from controls. Twelve of 36 patients received a diagnosis of MS within 3 years post-ADS. Patients with MS did not differ from children with monophasic ADS in terms of cognitive performance at the 6-months follow-up. Fatigue symptoms were reported in 50% of patients, irrespective of MS diagnosis. Presence of brain lesions at onset and 6 months post-incident demyelinating event did not associate with cognitive outcome. CONCLUSIONS: Children with ADS experience a favorable short-term neurocognitive outcome, even those confirmed to have MS. Longitudinal evaluations of children with monophasic ADS and MS are required to determine the possibility of late-emerging sequelae and their time course. (JINS, 2016, 22, 1050-1060).

Exposure to fluoridated water and attention deficit hyperactivity disorder prevalence among children and adolescents in the United States: an ecological association.

BACKGROUND: Epidemiological and animal-based studies have suggested that prenatal and postnatal fluoride exposure has adverse effects on neurodevelopment. The aim of this study was to examine the relationship between exposure to fluoridated water and Attention-Deficit Hyperactivity Disorder (ADHD) prevalence among children and adolescents in the United States. METHODS: Data on ADHD prevalence among 4-17 year olds collected in 2003, 2007 and 2011 as part of the National Survey of Children's Health, and state water fluoridation prevalence from the Centers for Disease Control and Prevention (CDC) collected between 1992 and 2008 were utilized. RESULTS: State prevalence of artificial water fluoridation in 1992 significantly positively predicted state prevalence of ADHD in 2003, 2007 and 2011, even after controlling for socioeconomic status. A multivariate regression analysis showed that after socioeconomic status was controlled each 1% increase in artificial fluoridation prevalence in 1992 was associated with approximately 67,000 to 131,000 additional ADHD diagnoses from 2003 to 2011. Overall state water fluoridation prevalence (not distinguishing between fluoridation types) was also significantly positively correlated with state prevalence of ADHD for all but one year examined. CONCLUSIONS: Parents reported higher rates of medically-diagnosed ADHD in their children in states in which a greater proportion of people receive fluoridated water from public water supplies. The relationship between fluoride exposure and ADHD warrants future study.

Age of onset as a moderator of cognitive decline in pediatric-onset multiple sclerosis.

Cognitive impairment is often reported in pediatric-onset multiple sclerosis (MS). Using serial cognitive data from 35 individuals with pediatric-onset MS, this study examined how age at disease-onset and proxies of cognitive reserve may impact cognitive maturation over the course of childhood and adolescence. Neuropsychological evaluations were conducted at baseline and up to four more assessments. Of the 35 participants, 7 completed only one assessment, 5 completed two assessments, 13 completed three assessments, 10 completed four or more assessments. Growth curve modeling was used to assess longitudinal trajectories on the Trail Making Test-Part B (TMT-B) and the Symbol Digit Modalities (SDMT; oral version) and to examine how age at disease onset, baseline Full Scale IQ, and social status may moderate rate of change on these measures. Mean number of evaluations completed per patient was 2.8. Younger age at disease onset was associated with a greater likelihood of cognitive decline on both the TMT-B (p=.001) and SDMT (p=.005). Baseline IQ and parental social status did not moderate any of the cognitive trajectories. Findings suggest that younger age at disease-onset increases the vulnerability for disrupted performance on measures of information processing, visual scanning, perceptual/motor speed, and working memory. Proxies of cognitive reserve did not protect against the progression of decline on these measures. Young patients with MS should be advised to seek follow-up cognitive evaluation to assess cognitive maturation and to screen for the potential late emergence of cognitive deficits. (JINS, 2014, 20, 1-9).

Fluoride exposure and thyroid hormone levels in pregnancy: The MIREC cohort.

BACKGROUND: Fluoride exposure may increase the risk of hypothyroidism, but results from previous studies are inconsistent at low-level fluoride exposure (i.e., ≤0.7 mg/L). Human studies of fluoride and thyroid hormone levels in pregnancy are scarce. OBJECTIVES: We examined associations between fluoride exposure and maternal thyroid hormone levels in a Canadian pregnancy cohort, with consideration for fetal sex-specific effects. METHODS: We measured fluoride concentrations in drinking water and spot urine samples collected during each trimester from 1876 pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study. We also measured maternal thyroid stimulating hormone (TSH), free thyroxine (FT4), and total thyroxine (TT4) levels during the first trimester of pregnancy. We used linear and non-linear regression models to estimate associations between fluoride exposure and levels of TSH, FT4, and TT4. We explored effect modification by fetal sex and considered maternal iodine status as a potential confounder. RESULTS: A 1 mg/L increase in urinary fluoride was associated with a 0.30 (95 %CI: 0.08, 0.51) logarithmic unit (i.e., 35.0 %) increase in TSH among women pregnant with females, but not males (B = 0.02; 95 %CI: -0.16, 0.19). Relative to women with urinary fluoride concentrations in the first quartile (0.05-0.32 mg/L), those with levels in the third quartile (0.49-0.75 mg/L) had higher FT4 and TT4 (i.e., inverted J-shaped associations), but the association was not statistically significant after adjustment for covariates (p = 0.06). Water fluoride concentration showed a U-shaped association with maternal FT4, whereby women with water fluoride concentrations in the second (0.13-0.52 mg/L) and third (0.52-0.62 mg/L) quartiles had significantly lower FT4 compared to those with levels in the first quartile (0.04-0.13 mg/L). Adjustment for maternal iodine status did not change the results. DISCUSSION: Fluoride exposure was associated with alterations in maternal thyroid hormone levels, the magnitude of which appeared to vary by fetal sex. Given the importance of maternal thyroid hormones for fetal neurodevelopment, replication of findings is warranted.