Fetal alcohol spectrum disorders in Finnish children and adolescents : diagnosis, cognition, behavior, adaptation and brain metabolic alterations

Alcohol consumption during pregnancy can potentially affect the developing fetus in devastating ways, leading to a range of physical, neurological, and behavioral alterations most accurately termed Fetal Alcohol Spectrum Disorders (FASD). Despite the fact that it is a preventable disorder, prenatal alcohol exposure today constitutes a leading cause of intellectual disability in the Western world. In Western countries where prevalence studies have been performed the rates of FASD exceed, for example, autism spectrum disorders, Down’s syndrome and cerebral palsy. In addition to the direct effects of alcohol, children and adolescents with FASD are often exposed to a double burden in life, as their neurological sequelae are accompanied by adverse living surroundings exposing them to further environmental risk. However, children with FASD today remain remarkably underdiagnosed by the health care system. This thesis forms part of a larger multinational research project, The Collaborative Initiative on Fetal Alcohol Spectrum Disorders (the CIFASD), initiated by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) in the U.S.A. The general aim of the present thesis was to examine a cohort of children and adolescents growing up with fetal alcohol-related damage in Finland. The thesis consists of five studies with a broad focus on diagnosis, cognition, behavior, adaptation and brain metabolic alterations in children and adolescents with FASD. The participants consisted of four different groups: one group with histories of prenatal exposure to alcohol, the FASD group; one IQ matched contrast group mostly consisting of children with specific learning disorder (SLD); and two typically-developing control groups (CON1 and CON2). Participants were identified through medical records, random sampling from the Finnish national population registry and email alerts to students. Importantly, the participants in the present studies comprise a group of very carefully clinically characterized children with FASD as the studies were performed in close collaboration with leading experts in the field (Prof. Edward Riley and Prof. Sarah Mattson, Center for Behavioral Teratology, San Diego State University, U.S.A; Prof. Eugene Hoyme, Sanford School of Medicine, University of South Dakota, U.S.A.). In the present thesis, the revised Institute of Medicine diagnostic criteria for FASD were tested on a Finnish population and found to be a reliable tool for differentiating among the subgroups of FASD. A weighted dysmorphology scoring system proved to be a valuable additional adjunct in quantification of growth deficits and dysmorphic features in children with FASD (Study 1). The purpose of Study 2 was to clarify the relationship between alcohol-related dysmorphic features and general cognitive capacity. Results showed a significant correlation between dysmorphic features and cognitive capacity, suggesting that children with more severe growth deficiency and dysmorphic features have more cognitive limitations. This association was, however, only moderate, indicating that physical markers and cognitive capacity not always go hand in hand in individuals with FASD. Behavioral problems in the FASD group proved substantial compared to the typically developing control group. In Study 3 risk and protective factors associated with behavioral problems in the FASD group were explored further focusing on diagnostic and environmental factors. Two groups with elevated risks for behavioral problems emerged: length of time spent in residential care and a low dysmorphology score proved to be the most pervasive risk factor for behavioral problems. The results underscore the clinical importance of appropriate services and care for less visibly alcohol affected children and highlight the need to attend to children with FASD being raised in institutions. With their background of early biological and psychological impairment compounded with less opportunity for a close and continuous caregiver relationship, such children seem to run an especially great risk of adverse life outcomes. Study 4 focused on adaptive abilities such as communication, daily living skills and social skills, in other words skills that are important for gradually enabling an independent life, maintain social relationships and allow the individual to become integrated into society. The results showed that adaptive abilities of children and adolescents growing up with FASD were significantly compromised compared to both typically-developing peers and IQ-matched children with SLD. Clearly different adaptive profiles were revealed where the FASD group performed worse than the SLD group, who in turn performed worse than the CON1 group. Importantly, the SLD group outperformed the FASD group on adaptive behavior in spite of comparable cognitive levels. This is the first study to compare adaptive abilities in a group of children and adolescents with FASD relative to both a contrast group of IQ-matched children with SLD and to a group of typically-developing peers. Finally, in Study 5, through magnetic resonance spectroscopic imaging (MRS) evidence of longstanding neurochemical alterations were observed in adolescents and young adults with FASD related to alcohol exposure in utero 14-20 years earlier. Neurochemical alterations were seen in several brain areas: in frontal and parietal cortices, corpus callosum, thalamus and frontal white matter areas as well as in the cerebellar dentate nucleus. The findings are compatible with neuropsychological findings in FASD. Glial cells seemed to be more affected than neurons. In conclusion, more societal efforts and resources should be focused on recognizing and diagnosing FASD, and supporting subgroups with elevated risk of poor outcome. Without adequate intervention children and adolescents with FASD run a great risk of marginalization and social maladjustment, costly not only to society but also to the lives of the many young people with FASD.

Dental Health in Preschool and Schoolchildren in Relation to Dental Fear and Some Fear-Related Factors, and the Outcome of a Caries Prevention Program in Offspring of Fearful Mothers

Dental caries and dental fear and anxiety (DFA) are common interrelated problems but so far little is known about these problems in Estonia. The aim was to study dental health in relation to DFA, some fear-related factors, and to study the effect of a caries prevention program in children of fearful mothers. Dental health and DFA were assessed in two Estonian [2-4-year-olds (n=472) and 8-10-year-olds (n=344)], and the effect of some medical conditions on DFA in one Finnish child group [3-year-olds (n=148)]. 120 mother-child-pairs participated in the xylitol-based prevention program. Dental health was examined using the WHO or the ICDAS criteria and expressed as dmft/DMFT-indices. The modified children’s fear survey schedule dental subscale (MCFSS-DS) was used to assess DFA of schoolchildren, one single question to assess parental DFA, and the Corah’s dental anxiety scale (DAS) to assess DFA of mothers in the prevention study. Dentine caries was diagnosed in 42% of the 2-4-year-old and in 93% of the 8-10-year-old Estonian children. DFA of 8-10-year-olds (17%) was associated with experience of dental treatment, and maternal and paternal DFA. Dental apprehension at 9 years of age was associated with frequent exposure to invasive medical care. The xylitol-based prevention was successful irrespective of poor dental hygiene habits and maternal severe DFA. In conclusion, experience of operative dental treatment and DFA of Estonian children were closely associated. Invasive medical care and parental DFA were also linked to children’s DFA. Habitual use of xylitol by mothers was effective in preventing caries even in children of severely fearful mothers.

Spontaneous Focusing on Quantitative Relations and the Development of Rational Number Conceptual Knowledge

The aim of the present set of studies was to explore primary school children’s Spontaneous Focusing On quantitative Relations (SFOR) and its role in the development of rational number conceptual knowledge. The specific goals were to determine if it was possible to identify a spontaneous quantitative focusing tendency that indexes children’s tendency to recognize and utilize quantitative relations in non-explicitly mathematical situations and to determine if this tendency has an impact on the development of rational number conceptual knowledge in late primary school. To this end, we report on six original empirical studies that measure SFOR in children ages five to thirteen years and the development of rational number conceptual knowledge in ten- to thirteen-year-olds. SFOR measures were developed to determine if there are substantial differences in SFOR that are not explained by the ability to use quantitative relations. A measure of children’s conceptual knowledge of the magnitude representations of rational numbers and the density of rational numbers is utilized to capture the process of conceptual change with rational numbers in late primary school students. Finally, SFOR tendency was examined in relation to the development of rational number conceptual knowledge in these students. Study I concerned the first attempts to measure individual differences in children’s spontaneous recognition and use of quantitative relations in 86 Finnish children from the ages of five to seven years. Results revealed that there were substantial inter-individual differences in the spontaneous recognition and use of quantitative relations in these tasks. This was particularly true for the oldest group of participants, who were in grade one (roughly seven years old). However, the study did not control for ability to solve the tasks using quantitative relations, so it was not clear if these differences were due to ability or SFOR. Study II more deeply investigated the nature of the two tasks reported in Study I, through the use of a stimulated-recall procedure examining children’s verbalizations of how they interpreted the tasks. Results reveal that participants were able to verbalize reasoning about their quantitative relational responses, but not their responses based on exact number. Furthermore, participants’ non-mathematical responses revealed a variety of other aspects, beyond quantitative relations and exact number, which participants focused on in completing the tasks. These results suggest that exact number may be more easily perceived than quantitative relations. As well, these tasks were revealed to contain both mathematical and non-mathematical aspects which were interpreted by the participants as relevant. Study III investigated individual differences in SFOR 84 children, ages five to nine, from the US and is the first to report on the connection between SFOR and other mathematical abilities. The cross-sectional data revealed that there were individual differences in SFOR. Importantly, these differences were not entirely explained by the ability to solve the tasks using quantitative relations, suggesting that SFOR is partially independent from the ability to use quantitative relations. In other words, the lack of use of quantitative relations on the SFOR tasks was not solely due to participants being unable to solve the tasks using quantitative relations, but due to a lack of the spontaneous attention to the quantitative relations in the tasks. Furthermore, SFOR tendency was found to be related to arithmetic fluency among these participants. This is the first evidence to suggest that SFOR may be a partially distinct aspect of children’s existing mathematical competences. Study IV presented a follow-up study of the first graders who participated in Studies I and II, examining SFOR tendency as a predictor of their conceptual knowledge of fraction magnitudes in fourth grade. Results revealed that first graders’ SFOR tendency was a unique predictor of fraction conceptual knowledge in fourth grade, even after controlling for general mathematical skills. These results are the first to suggest that SFOR tendency may play a role in the development of rational number conceptual knowledge. Study V presents a longitudinal study of the development of 263 Finnish students’ rational number conceptual knowledge over a one year period. During this time participants completed a measure of conceptual knowledge of the magnitude representations and the density of rational numbers at three time points. First, a Latent Profile Analysis indicated that a four-class model, differentiating between those participants with high magnitude comparison and density knowledge, was the most appropriate. A Latent Transition Analysis reveal that few students display sustained conceptual change with density concepts, though conceptual change with magnitude representations is present in this group. Overall, this study indicated that there were severe deficiencies in conceptual knowledge of rational numbers, especially concepts of density. The longitudinal Study VI presented a synthesis of the previous studies in order to specifically detail the role of SFOR tendency in the development of rational number conceptual knowledge. Thus, the same participants from Study V completed a measure of SFOR, along with the rational number test, including a fourth time point. Results reveal that SFOR tendency was a predictor of rational number conceptual knowledge after two school years, even after taking into consideration prior rational number knowledge (through the use of residualized SFOR scores), arithmetic fluency, and non-verbal intelligence. Furthermore, those participants with higher-than-expected SFOR scores improved significantly more on magnitude representation and density concepts over the four time points. These results indicate that SFOR tendency is a strong predictor of rational number conceptual development in late primary school children. The results of the six studies reveal that within children’s existing mathematical competences there can be identified a spontaneous quantitative focusing tendency named spontaneous focusing on quantitative relations. Furthermore, this tendency is found to play a role in the development of rational number conceptual knowledge in primary school children. Results suggest that conceptual change with the magnitude representations and density of rational numbers is rare among this group of students. However, those children who are more likely to notice and use quantitative relations in situations that are not explicitly mathematical seem to have an advantage in the development of rational number conceptual knowledge. It may be that these students gain quantitative more and qualitatively better self-initiated deliberate practice with quantitative relations in everyday situations due to an increased SFOR tendency. This suggests that it may be important to promote this type of mathematical activity in teaching rational numbers. Furthermore, these results suggest that there may be a series of spontaneous quantitative focusing tendencies that have an impact on mathematical development throughout the learning trajectory.

The Use of Nervous System Drugs and the Risk of Fractures in Old Adults

Hermostoon vaikuttavien lääkkeiden käyttö on yleistä iäkkäässä väestössä. Erityisen yleistä käyttö on pitkäaikaisessa laitoshoidossa asuvilla iäkkäillä. Hermostoon vaikuttavien lääkkeiden haittavaikutuksia on tutkittu paljon, ja useat hermostoon vaikuttavat lääkeaineryhmät on tunnistettu murtumien riskitekijöiksi. Aikaisemmin ei ole kuitenkaan tutkittu usean hermostoon vaikuttavan lääkkeen yhteiskäytön yhteyksiä murtuman riskiin 65 vuotta täyttäneillä. Väitöskirjatutkimuksessa havaittiin, että usean hermostoon vaikuttavan lääkeaineen yhtäaikainen käyttö oli hyvin yleistä Porin kaupunginsairaalan viidellä pitkäaikaisen laitoshoidon osastolla (n = 154) vuosien 2004 ja 2005 vaihteessa. Kolmasosa tutkituista käytti säännöllisesti kolmea tai useampaa hermostoon vaikuttavaa lääkettä samanaikaisesti. Kun huomioitiin myös tarvittaessa otettavat lääkkeet, vastaava luku oli 53 %. Tutkimuksessa havaittiin myös viitteitä lääkkeiden epäasianmukaisesta käytöstä, kun potilaiden käyttämiä lääkkeitä verrattiin heidän kognitiiviseen ja fyysiseen suorituskyynsä sekä asetettuihin diagnooseihin. Liedon kunnassa 1990-luvulla toteutettuun väestöpohjaiseen Liedon Iäkkäät -seurantatutkimukseen osallistui 1177 lietolaista 65 vuotta täyttänyttä. Lääkitystietoja sekä seuranta-aikana tapahtuneita murtumia analysoimalla havaittiin, että kahden tai useamman bentsodiatsepiinin sekä kahden tai useamman psykoosilääkkeen käyttö oli yhteydessä murtuman riskiin 65 vuotta täyttäneillä miehillä. Opioidin ja psykoosilääkkeen yhteiskäyttö sekä opioidin ja bentsodiatsepiinin yhteiskäyttö oli yhteydessä iäkkäiden miesten murtuman riskiin. Naisilla vastaavia tilastollisesti merkitseviä yhteyksiä ei havaittu. Väitöskirjatutkimuksen uusin osa-aineisto perustui Porissa vuosina 2009–2010 toteutetun Satauni-tutkimuksen aineistoon. Tutkimuksessa osoitettiin 89 potilaan aineistossa, että hallittu, yhden kuukauden aikana lääkärin ja hoitajan tuella toteutettu bentsodiatsepiinivieroitus paransi merkitsevästi 55 vuotta täyttäneiden naisten käden puristusvoimaa kuuden kuukauden seuranta-aikana. Vastaavaa yhteyttä ei havaittu miehillä. Bentsodiatsepiinivieroituksella ei ollut yhteyttä osallistujien tasapainotestin tulosten paranemiseen kuuden kuukauden seurantaaikana. Murtumilla on vakavia seurauksia sekä yksilötasolla että yhteiskunnallisesti iäkkäässä väestössä. Murtumien ehkäisy on hyvin tärkeää. Siinä tulee kiinnittää huomiota potilaan käyttämään lääkitykseen ja arvioida erityisesti usean hermostoon vaikuttavan lääkkeen yhteiskäytön tarpeellisuutta.

Determinants of Bone Strength and Predictors of Hip Fracture among Finnish Adults. Results from the Health 2000 Survey and the Mini-Finland Health Survey

The objective of this thesis was to identify the determinants of bone strength and predictors of hip fracture in representative samples of Finnish adults. A secondary objective was to construct a simple multifactorial model for hip fracture prediction over a 10-year follow-up period. The study was based on the Health 2000 Survey conducted during 2000 to 2001 (men and women aged 30 years or over, n=6 035) and the Mini-Finland Health Survey conducted during 1978 to 1980 (women aged 45 years or over, n=2 039). Study subjects participated in health interviews and comprehensive health examination. In the Health 2000 Survey, bone strength was assessed by means of calcaneal quantitative ultrasound (QUS). The follow-up information about hip fractures was drawn from the National Hospital Discharge Register. In this study, age, weight, height, serum 25-hydroxyvitamin D (S-25(OH)D), physical activity, smoking and alcohol consumption as well as menopause and eventual HRT in women were found to be associated with calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS). Parity was associated with a decreased risk of hip fracture in postmenopausal women. Age, height, weight or waist circumference, quantitative ultrasound index (QUI), S-25(OH)D and fall-related factors, such as maximal walking speed, Parkinson’s disease, and the number of prescribed CNS active medication were significant independent predictors of hip fracture. At the population level, the incremental value of QUS appeared to be minor in hip fracture prediction when the fall-related risk factors were taken into account. A simple multifactorial model for hip fracture prediction presented in this study was based on readily available factors (age, gender, height, waist circumference, and fallrelated factors). Prospective studies are needed to test this model in patient-based study populations.