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.

Smoking during pregnancy and fetal brain development

Background: Although the knowledge of adverse effects of smoking during pregnancy has increased in recent years, more research is needed to gain a better understanding of the effects of smoking during pregnancy. Smoking exposure is the most common preventable factor that causes adverse pregnancy outcomes. Aims and Methods: First, data on smoking habits during pregnancy from the Nordic Medical Birth Registers was used to study the national differences in trends of smoking during pregnancy. Second, the effects of prenatal smoking exposure on fetal brain development, assessed by brain MRI at term age, were studied by using data from the multidisciplinary PIPARI Study consisting of a 6-year cohort of VLBW/VLGA infants (n = 232, of which 18.1% were exposed to prenatal smoking) born in Turku University Hospital, Finland. Third, the effects of prenatal smoking exposure on psychiatric morbidity and use of psychotropic medication were studied in a cohort of children born from 1987–1989 in Finland (n = 175,869, of which 15.3% were exposed). The data used were obtained from population-based longitudinal registers from the National Institute of Health and Welfare, the Statistics Finland, and the Finnish Social Insurance Institution. Results: Smoking rates during pregnancy differed considerably between the countries. Smoking rates were highest among teenagers and women with lower socioeconomic positions. The smoking prevalence was found to be increasing among teenagers in both Finland and Norway. Prenatal smoking exposure was associated with smaller frontal lobe and cerebellar volumes in preterm infants. A clear association was found between prenatal smoking exposure and psychiatric morbidity treated with specialized hospital care and the use of various psychotropic medications. Conclusions: Prenatal smoking exposure had adverse effects on fetal brain development. These effects might explain part of the association found between smoking exposure and psychiatric problems in later life. Our study suggests that prenatal smoking exposure is linked with both mild and severe psychiatric problems. This study emphasizes the importance of efforts to reduce smoking during pregnancy.

Congenital upper limb defects in Finland 1993-2005

Background: Interest in limb defects has grown after the thalidomide tragedy in the 1960s. As a result, congenital malformation registries, monitoring changes in birthprevalence and defect patterns, have been established in several countries. However, there are only a few true population based studies on birth prevalence of upper limb defects. The burden of hospital care among these children, specifically in terms of the number of admissions and total time spent in hospital, is also unknown. Aims and Methods: This study is based on information gathered from the Finnish Register of Congenital malformations (FRM) and the Finnish Hospital Discharge Register (FHDR). A total of 417 children born between 1993 and 2005 with an upper limb defect were gathered from the FRM. The upper limb defects were classified using the International Federation of Societies for Surgery of the Hand -classification that enables comparison with previous and future studies. Birth and live birth prevalence, sex and side distribution, frequency of associated anomalies as well as the proportion of perinatal and infant deaths according to the different subtypes were calculated. The number of hospital admissions, days spent in hospital, number and type of surgical operations were collected from the FHDR. Special features of two subgroups, radial ray defects (RRD) and constriction band syndrome (CBS), were explored. Results: Upper limb defects were observed in 417 of 753 342 consecutive births and in 392 of 750 461 live births. Birth prevalence was 5.5 per 10 000 births and 5.2 per 10 000 live births. Multiple anomalies or a known syndrome was found in 250 cases (60%). Perinatal mortality was 139 per 1000 births and infant mortality 135 per 1000 live births (overall Finnish perinatal mortality <5 per 1000 births and infant mortality 3.7 per 1000 live births). Altogether, 138 infants had RRD and 120 (87%) of these had either a known syndrome or multiple major anomalies. The proportion of perinatal deaths in RRD group was 29% (40/138) and infant deaths 35% (43/123). Fifty-one children had CBS in upper limbs. Fifteen of these (29%) had other major anomalies associated with constriction rings. The number of hospital admissions per year of children with congenital upper limb defects was 11-fold and the time spent in hospital 13-fold as compared with the general paediatric population. Conclusions: Birth prevalence of congenital upper limb defects was 5.5 per 10 000 births and 5.2 per 10 000 live births. RRD was especially associated with other major anomalies and high mortality. Nearly one third of the children with CBS also had other major anomalies suggesting different aetiologies inside the group. The annual burden of hospital care of children with congenital upper limb defects was at least 11-fold as compared with the general paediatric population.