Do children with congenital hypothyroidism exhibit abnormal cortical morphology?

BACKGROUND: Given thyroid hormone (TH)'s essential role in multiple aspects of early brain development, children with congenital hypothyroidism (CH) detected and treated early may still display subtle cognitive and behavioral impairments as well as brain abnormalities. However, effects on their cortical development are not yet known. We used an automated neuroimaging technique to determine if these children differ in cortical thickness (CT) from typically developing controls (TDC) and if the regions showing CT differences reflect severity of initial hypothyroidism and predict later neuropsychological functioning. METHODS: FreeSurfer Image Analysis Suite was used on archived MRI scans from 41 CH and 42 TDC children aged 9-16 y. Vertex-based procedures were used to compare groups and perform correlations between CT and indices of disease severity and neuropsychological outcome. RESULTS: The CH group showed multiple regions of cortical thinning or cortical thickening within right and left hemispheres relative to TDC. CT values were significantly correlated with early T4 and thyroid-stimulating hormone (TSH) levels and current neuropsychological test indices. CONCLUSION: The developing cortex is sensitive to early TH loss in CH. Different patterns of cortical thinning or cortical thickening among brain regions may reflect timing of TH deficiency relative to timing of cortical development.

Social Perspective Taking and Empathy in Children with Fetal Alcohol Spectrum Disorders.

Children with fetal alcohol spectrum disorders (FASD) show sociobehavioral impairments; however, the social cognitive profile contributing to these impairments is poorly understood. This study compared social perspective taking and empathy in children with FASD versus typically developing controls (TDC). Thirty-seven children with FASD and 21 TDC participated. Measures included parent-rated CBCL and SSIS, and NEPSY-II Theory of Mind, Test of Social Cognition and Index of Empathy. Parents rated the FASD group higher than TDC on indices of behavior problems and lower on indices of social skills and empathy. Children with FASD scored significantly below TDC on tasks requiring complex social cognition. The majority of correlations between social cognition and parent-ratings were not significant in FASD and TDC, with the exception of a negative correlation between self-reported empathy and parent-rated behavior difficulties in TDC. FASD subgroup analyses revealed lower theory of mind and empathy scores among children with ARND than pFAS/FAS. With regard to sex, males with FASD were rated as having more behavior difficulties than females, whereas TDC females obtained higher empathy ratings than males. In both groups, females scored higher on theory of mind and empathy indices. On theory of mind tasks, older children with FASD performed below younger, whereas younger TDC children performed more poorly than older. Children with FASD show reduced functioning on indices of sociobehavioral and social cognition, and the effects are influenced by sex and age. These findings provide insight into the clinical and social profile of children with FASD.

Hippocampal abnormalities in youth with alcohol-related neurodevelopmental disorder.

Individuals diagnosed with alcohol-related neurodevelopmental disorder (ARND) exhibit difficulty on hippocampally mediated memory tasks and show reduced hippocampal size. However inconsistencies exist regarding the affected memory functions and where within the hippocampi effects occur. Given recent studies showing anterior and posterior segments support distinct memory functions and sex dimorphisms in hippocampal function, we asked whether these factors influence memory performance in youth with ARND (n = 18) and typically developing controls (n = 17). Participants received a battery of memory tests and a structural MRI scan. Right and left hippocampi were manually traced; anterior and posterior segments were delineated at the uncus. Measured were intracranial volumes (ICV) and right and left hippocampi and hippocampal segments. Volumes were adjusted for ICV. Relative to controls, the ARND group had lower IQs and memory performance on most tasks and marginally smaller ICVs. Left and right hippocampal volumes and posterior segments were smaller in the ARND group. Although no sex differences were observed between groups, females overall had larger anterior hippocampi than males. Positive and negative associations between hippocampal and selective memory indices were found in the ARND group only. These findings are the first to suggest that posterior hippocampal development may be compromised in youth with ARND.

Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5).

BACKGROUND: The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) showed no benefit in the reduction of major neonatal mortality/morbidity or neurodevelopment at 2 and 5 years of age. Using the data from the randomized controlled trial and its follow-up, the aim of this study was to evaluate the association between gestational ages at birth in children exposed to single versus multiple courses of antenatal corticosteroid (ACS) therapy in utero and outcomes at 5 years of age. METHOD: A total of 1719 children, with the breakdown into groupings of <30, 30-36, and ≥ 37 weeks gestation at birth, contributed to the primary outcome: death or survival with a disability in one of the following domains: neuromotor, neurosensory, and neurobehavioral/emotional disability and were included in this analysis. RESULTS: Gestational age at birth was strongly associated with the primary outcome, p < 0.001. Overall, the interaction between ACS groups and gestational age at birth was not significant, p = 0.064. Specifically, in the 2 preterm categories, there was no difference in the primary outcome between single vs. multiple ACS therapy. However, for infants born ≥37 weeks gestation, there was a statistically significant increase in the risk of the primary outcome in multiple ACS therapy, 48/213 (22.5%) compared to 38/249 (15.3%) in the single ACS therapy; OR = 1.69 [95% CI: 1.04, 2.77]; p = 0.037. CONCLUSION: Preterm birth (<37 weeks gestation) remained the primary factor contributing to an adverse outcome regardless of the number of courses of ACS therapy. Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an increased risk of neurodevelopmental/neurosensory impairment by 5 years of age. To optimize outcomes for infants/children, efforts in reducing the incidence of preterm birth should remain the primary focus in perinatal research. TRIAL REGISTRATION: This study has been registered at (identifier NCT00187382).

Targeting the Manifestations of Subclinical and Overt Hypothyroidism Within the Hippocampus.

BACKGROUND: The past decade has witnessed a surge of articles describing the neurocognitive sequelae and associated structural and functional brain abnormalities of patients with overt (OH) and subclinical hypothyroidism (SCH). Findings show effects primarily within the frontal lobes with usually worse outcomes for OH than SCH. Several recent studies have also indicated hypothyroid patients may have smaller hippocampi, a key structure for memory. CONTEXT: The current JCEM paper by T. Zhang and colleagues applies two novel approaches for analyzing hippocampal structure and function. One uses an automated processing tool that segments the hippocampus into distinct subregions and the other, performs connectivity analysis to assess the relationships between specific hippocampal subregions and cortical areas. Relatively large samples of OH and SCH patients and healthy controls received a test of global cognitive functioning and structural and functional MRIs. Results showed hypothyroid groups scored significantly below controls on the memory scale and also had smaller hippocampal volumes in selective subregions. Effects were stronger for SCH than OH groups, who also showed different patterns of interconnectivity between hippocampal subregions and specific frontal-lobe areas. INTERPRETATION: To make sense of these findings, I explored the rodent and human literatures on thyroid hormone's role in hippocampal functioning and on hippocampal subfields and their purported functions and interconnections. Because current results suggest SCH may represent a distinct clinical entity with unique brain manifestations, I hypothesized two explanations for these findings, one involving transporter defects in the brain barriers and the other, differential neurodegeneration of the blood-brain-barrier vascular unit.

Visuospatial, visuoperceptual, and visuoconstructive abilities in congenital hypothyroidism.

Individuals with congenital hypothyroidism (CH), even those diagnosed and treated early, experience selective cognitive deficits, the most striking of which involves the visuocognitive domain. However, the range and nature of their visuocognitive disturbances is not fully understood. We assessed a range of higher-order visuocognitive abilities in 19 children and adolescents with CH and 19 age- and sex-matched typically developing peers (TD) using a battery of neuropsychological tests and a novel self-report measure of sense of direction. CH scored lower than TD on direct tests of visuocognitive function (judging line orientation, parts-to-whole localization, copying three-dimensional block towers, discriminating designs, and matching unfamiliar faces in ¾ profile-view) as well as on self-reported problems in spatial ability. Visuocognitive problems were not global as CH and TD did not differ at copying two-dimensional block designs, mentally rotating and matching abstract shapes, or at matching unfamiliar front-view faces, design features, or designs that engaged either figure-ground segregation, visual constancy, or closure. Early and concurrent thyroid stimulating hormone (TSH) levels were associated with visuocognitive ability, although attention and working memory were not. Individuals with CH exhibit selective visuocognitive weaknesses, some of which are related to early and concurrent TSH levels.

Effects of early thyroid hormone deficiency on children's autobiographical memory performance.

Memory deficits and hippocampal abnormalities have been described in individuals with thyroid hormone (TH) insufficiencies; however, no study has yet examined their autobiographical memory (AM) abilities, which are known to be compromised by hippocampal damage. Investigations in adults have shown that AM consists of both episodic and semantic components and that the hippocampus is preferentially involved in episodic AM. The present study used the Children's Autobiographical Interview (CAI) to study episodic and semantic AM in 79 children aged 9 to 14 years, including 26 with early-treated congenital hypothyroidism (CH), 23 born to women with inadequately treated hypothyroidism during pregnancy (HYPO), and 30 typically developing controls. Results showed that relative to controls, CH and HYPO groups both exhibited weaknesses in episodic AM, but not semantic AM. In particular, CH and HYPO groups showed difficulty in recalling event details (i.e., the main happenings) and visual details from past experiences. Overall, this study highlights the importance of TH for early neurodevelopment and provides critical new insight into the effects of early treated TH deficiency on long-term memory performance. Furthermore, the present study indicates that the CAI is an effective tool for investigating episodic AM impairment in clinical pediatric populations.

Children with congenital hypothyroidism have similar neuroradiological abnormal findings as healthy ones.

OBJECTIVE: To assess the neuroradiological findings of children with congenital hypothyroidism (CHT) compared to healthy controls (HC). PATIENTS AND METHODS: Thirty children with CHT, mean age 12.5 ± 1.6 years, 14 (44.8%) males, were compared with 38 HC mean age 11.7 ± 1.7 years, 16 (45.7%) males. Clinical data were collected from medical charts and questionnaires seeking information on family history, birth and perinatal period events, medications, and overall health history. Neurocognitive function was assessed for global intelligence, visual and verbal memory, and executive functioning using standardized tests. Neuroimaging was performed using 1.5 T magnetic resonance imaging and assessed by two pediatric radiologists. RESULTS: Children with CHT had a similar proportion of incidental findings as did the children in the HC group, at 43.3% and 39.5%, respectively, P = 0.69. Abnormalities of the sellar region were reported in 13.3% of CHT group and 7.9% of HC group, P = 0.46. Other incidental findings included cerebellar ectopia, choroidal fissure and pineal cysts, and multiple increased signal intensity foci. Neuroradiological findings were not associated with clinical and neurocognitive abnormalities. CONCLUSION: Neuroimaging of children with CHT demonstrated a similar incidence of structural abnormalities as in the healthy population. There is no association between those findings and neurocognitive function.

Visuospatial associative memory and hippocampal functioning in congenital hypothyroidism.

Congenital hypothyroidism is a pediatric endocrine disorder caused by insufficient endogenous thyroid hormone production. Children with congenital hypothyroidism have difficulties with episodic memory and abnormalities in hippocampal structure, suggesting deficient hippocampal functioning. To assess hippocampal activation in adolescents with congenital hypothyroidism (N = 14; age range, 11.5-14.7 years) compared with controls (N = 15; age range, 11.2-15.5 years), a functional magnetic resonance imaging visuospatial memory task was used. In this task, participants had to decide if object pairings were novel or were previously studied or if object pairs were in the same location as they were at study or had switched locations. Despite no group differences in task performance, adolescents with congenital hypothyroidism showed both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls. Furthermore, the increased activation in the congenital hypothyroidism group was correlated with the severity of the hypothyroidism experienced early in life. These results suggest that perinatal deprivation of thyroid hormone has longstanding effects on hippocampal function and may account for memory problems experienced by adolescents with congenital hypothyroidism.

Long-term neurodevelopment of children exposed to maternal nausea and vomiting of pregnancy and diclectin.

OBJECTIVE: To determine the effects of nausea and vomiting of pregnancy (NVP) and its treatment with diclectin on child neurodevelopment. STUDY DESIGN: An observational cohort study of mother-child pairs ascertained via a pregnancy call-in center was conducted. Three groups of children were studied: 45 with NVP and diclectin, 47 with NVP no diclectin, and 29 with no NVP. Phone calls to mothers during pregnancy and 6 to 9 months after childbirth yielded information on pregnancy, birth, and early child development. Children aged 3 to 7 years received a comprehensive set of psychological tests. Mothers were assessed for IQ and socioeconomic status. RESULTS: All children scored in the normal range for IQ, with the NVP-exposed group scoring higher than the non-exposed group on Performance IQ (P < .02), NEPSY Verbal Fluency (P < .003) and Phonological Processing (P < .004), and McCarthy Numerical Memory (P < .004). Predictors of enhanced results were NVP severity and maternal IQ. CONCLUSIONS: NVP has an enhancing effect on later child outcome. Diclectin does not appear to adversely affect fetal brain development and can be used to control NVP when clinically indicated.

Social cognitive and emotion processing abilities of children with fetal alcohol spectrum disorders: a comparison with attention deficit hyperactivity disorder.

BACKGROUND: Although children with Fetal Alcohol Spectrum Disorders (FASDs) are at high risk of attention deficit hyperactivity disorder (ADHD), direct comparisons show distinct cognitive phenotypes in the 2 diagnoses. However, these groups have not been directly compared for social problems or social cognition, nor has social cognition been directly examined in FASDs. OBJECTIVES: To compare FASDs and ADHD groups on social cognition tasks and determine whether deficient social cognition and emotion processing predict behavioral problems and social skills. METHODS: Studied were 33 children with FASDs, 30 with ADHD, and 34 normal controls (NC). All received tasks of social cognition and emotion processing. Parents and teachers rated children on measures of completed questionnaires assessing child's behavioral problems and social skills using the Child Behavior Checklist, Teacher Report Form, and Social Skills Rating Scale. Children received 3 subtests from the Saltzman-Benaiah and Lalonde (2007) Theory of Mind Task as a measure of social cognition and 4 subtests from the Minnesota Test of Affective Processing (Lai et al., 1991) to assess emotion processing. RESULTS: Parents and teachers reported more behavior problems and poorer social skills in children in FASD and ADHD than NC groups. FASDs demonstrated significantly weaker social cognition and facial emotion processing ability than ADHD and NC groups. Regression analyses identified social cognition as a significant predictor of behavior problems and emotion processing as a significant predictor of social skills. CONCLUSIONS: Children with FASDs show a distinct behavioral profile from children with ADHD. Difficulties in social cognition and emotion processing in children with FASDs may contribute to their high incidence of social behavioral problems.

Growth and body composition of human milk-fed premature infants provided with extra energy and nutrients early after hospital discharge: 1-year follow-up.

OBJECTIVES: Human milk (HM) is the optimal source of nutrition for premature infants; however, it is unclear whether HM alone is sufficient to meet their elevated nutritional requirements early after hospital discharge. We previously reported that premature infants (750-1800 g birth weight) fed HM containing extra nutrients for 12 weeks after discharge had dietary intakes closer to recommended levels and grew more rapidly than those fed HM alone. The objectives of the present article are to examine the impact of this intervention on bone mineralization, body composition, and HM use up to 1 year. Data are also presented on general developmental level at 18-month corrected age (CA). PATIENTS AND METHODS: At discharge, predominantly HM-fed infants were randomized to receive for 12 weeks either approximately half of their feedings containing a multinutrient fortifier (intervention, n=19) or all of their feedings as HM alone (control, n=20). RESULTS: Intervention infants remained longer (P<0.001) and had greater whole-body bone mineral content (P=0.02) until 12-month CA compared with controls. Intervention infants born less than or equal to 1250 g continued to have a larger mean head circumference throughout the first year of life (P<0.0001). Human milk feeding (mL.kg(-1).day(-1)) differed between groups at 6- (P=0.035), but not 12-month CA. No statistically significant differences were found between groups in the mental, motor, or behavior rating scale scores of the Bayley II at 18-month CA. CONCLUSIONS: Adding a multinutrient fortifier to HM provided to predominantly HM-fed premature infants early after discharge results in sustained differences in weight, length, and whole-body bone mineral content, and in smaller babies, head circumference for the first year of life.

Growth Hormone Supplementation and Psychosocial Functioning to Adult Height in Turner Syndrome: A Questionnaire Study of Participants in the Canadian Randomized Trial.

Despite the long-held belief that growth hormone supplementation provides psychosocial benefits to patients with Turner syndrome (TS), this assumption has never been rigorously tested in a randomized control trial. As a sub-study of the Canadian growth-hormone trial, parent-, and patient-completed standardized questionnaires were used to compare 70 girls with TS who received injections (GH group) and 61 similarly followed untreated TS controls (C) on multiple facets of psychosocial functioning. Questionnaires were given (i) at baseline (session 1, mean age = 10.4 y), (ii) before estrogen therapy for puberty induction (session 2, mean age = 13.0 y), (iii) after 1 year of estrogen therapy (session 3, mean age = 14.4 y), and (iv) when growth stopped (session 4, mean age = 16.3 y). Groups were compared for multiple facets of psychosocial function within social, behavioral, self-esteem, and academic domains. Results were also correlated with indices of adult height. We found no global (i.e., across-session) group differences on any scales or subscales of the four domains. In both GH and C groups, age-related improvements were seen for social problems, externalizing behavior problems, and school functioning and age-related declines for social competence and social relations. Both parents and patients claimed GH received less teasing than C but C had more friends than GH. Results from analyses conducted within individual sessions showed that while GH at early sessions claimed to be more popular, more socially engaged, better adapted, and to have higher self-esteem than C, C was reported to be less anxious, depressed, and withdrawn than GH at adult height. The correlation analyses revealed different effects of adult height and height gain on outcome for the two groups. In GH, both height parameters were correlated with multiple parent- and/or self-reported indices from the four psychosocial domains, whereas in C, only adult height and two indices (viz., total self-concept and school functioning), were correlated. The observed modest gains in psychosocial functioning for patients with TS treated with GH highlight the need for alternative approaches to assist them in coping with the challenges of their condition.

Everyday memory difficulties in children and adolescents with Fetal Alcohol Spectrum Disorder.

Purpose: To investigate whether significant differences exist in everyday memory between youth with Fetal Alcohol Spectrum (FASD) compared with a nonexposed (NE) control group, while controlling for socioeconomic status and other comorbidities. Methods: Caregiver ratings using the Everyday Memory Questionnaire were obtained for 105 youth (9-17 years of age). Scores were compared between youth with a FASD diagnosis (N = 41; 56% male) and the NE group (N = 64; 53% male) using multivariate analysis of variance. Results: Significantly poorer scores were found across all domains of everyday memory in youth with FASD (p<0.01 for all comparisons). Findings maintained significance after controlling for group differences in socioeconomic status, presence of learning, and attention disorders, as well as exposure to other teratogens. Conclusions: This study provides important insights regarding the memory issues that underlie daily functional challenges faced by youth with FASD and the need for future intervention research.

Meeting report: measuring endocrine-sensitive endpoints within the first years of life.

An international workshop titled "Assessing Endocrine-Related Endpoints within the First Years of Life" was held 30 April-1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions.

Effects of prenatal alcohol exposure on hippocampal volume, verbal learning, and verbal and spatial recall in late childhood.

Children with prenatal alcohol exposure (PAE) show deficits in verbal learning and spatial memory, as well as abnormal hippocampal development. The relationship between their memory and neuroanatomic impairments, however, has not been directly explored. Given that the hippocampus is integral for the synthesis and retrieval of learned information and is particularly vulnerable to the teratogenic effects of alcohol, we assessed whether reduced learning and recall abilities in children with fetal alcohol spectrum disorders (FASDs) are associated with abnormal hippocampal volumes. Nineteen children with FASDs and 18 typically developing controls aged 9 to 15 years were assessed for verbal learning and verbal and spatial recall and underwent structural magnetic resonance imaging. Images were analyzed for total intracranial volume and for right and left hippocampal volumes. Results revealed smaller left hippocampi and poorer verbal learning and verbal and spatial recall performance in children with FASDs than controls, as well as positive correlations between selective memory indices and hippocampal volumes only in the FASD group. Additionally, hippocampal volumes increased significantly with age in controls only, suggesting that PAE may be associated with long-term abnormalities in hippocampal development that may contribute to impaired verbal learning and verbal and spatial recall.

Workplace standards for exposure to toxicants during pregnancy.

Many women of childbearing age are exposed to reproductive toxicants in the workplace. This article highlights the need for an evaluation of current occupational exposure guidelines for pregnant women working with hazardous agents that have the potential of being reproductive toxins. Limited information regarding reproductive risks associated with many chemicals in the workplace presents challenges in the establishment of standards that are 'safe' for vulnerable populations, such as the fetus. The management of these risks must take into consideration the limitations of available knowledge as well as individual risk factors that may amplify the likelihood of adverse outcomes. In 1981, Quebec adopted a policy that provides "precautionary leave" or reassignment of pregnant workers to other jobs if they are exposed to a factor suspected to compromise their health or that of their fetus during pregnancy. The advantages and disadvantages of this approach to managing reproductive hazards are discussed. The existence of a regulatory safety net at the level of the workplace for minimizing the impact of toxicant exposure on reproductive health outcomes is stressed. Management options that can be implemented early to provide added protection when a hazard cannot be reduced or eliminated are recommended.

Understanding fetal alcohol spectrum disorders (FASDs): toward identification of a behavioral phenotype.

Fetal alcohol spectrum disorders (FASDs) currently represent the leading cause of mental retardation in North America, ahead of Down syndrome and cerebral palsy. The damaging effects of alcohol on the developing brain have a cascading impact on the social and neurocognitive profiles of affected individuals. Researchers investigating the profiles of children with FASDs have found impairments in learning and memory, executive functioning, and language, as well as hyperactivity, impulsivity, poor communication skills, difficulties with social and moral reasoning, and psychopathology. The primary goal of this review paper is to examine current issues pertaining to the identification of a behavioral phenotype in FASDs, as well as to address related screening and diagnostic concerns. We conclude that future research initiatives comparing children with FASDs to nonalcohol-exposed children with similar cognitive and socioemotional profiles should aid in uncovering the unique behavioral phenotype for FASDs.

Novel approaches to the diagnosis of fetal alcohol spectrum disorder.

The diagnosis of fetal alcohol spectrum disorder is a difficult task, especially in cases where clear, physical markers of in utero alcohol exposure are not apparent. Reviewed in the following paper are some older tools for screening alcohol use in pregnancy and present novel approaches to the diagnosis of FASD, including ethanol biomarker development to behavioural phenotyping. Improving current FASD diagnostic methodology through more novel approaches may provide the possibility of earlier and wider diagnosis, allowing intervention and treatment at stages where the advanced effects of alcohol can still be mitigated.