Practitioner Review: What have we learnt about the causes of ADHD?

Background: Attention deficit hyperactivity disorder (ADHD) and its possible causes still attract controversy. Genes, pre and perinatal risks, psychosocial factors and environmental toxins have all been considered as potential risk factors. Method: This review (focussing on literature published since 1997, selected from a search of PubMed) critically considers putative risk factors with a focus on genetics and selected environmental risks, examines their relationships with ADHD and discusses the likelihood that these risks are causal as well as some of the main implications. Results: No single risk factor explains ADHD. Both inherited and noninherited factors contribute and their effects are interdependent. ADHD is familial and heritable. Research into the inherited and molecular genetic contributions to ADHD suggest an important overlap with other neurodevelopmental problems, notably, autism spectrum disorders. Having a biological relative with ADHD, large, rare copy number variants, some small effect size candidate gene variants, extreme early adversity, pre and postnatal exposure to lead and low birth weight/prematurity have been most consistently found as risk factors, but none are yet known to be definitely causal. There is a large literature documenting associations between ADHD and a wide variety of putative environmental risks that can, at present, only be regarded as correlates. Findings from research designs that go beyond simply testing for association are beginning to contest the robustness of some environmental exposures previously thought to be ADHD risk factors. Conclusions: The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history. There is a need to consider the possibility of parents and siblings being similarly affected and how this might impact on engagement with families, influence interventions and require integration with adult services. Genetic contributions to disorder do not necessarily mean that medications are the treatment of choice. We also consider how findings might influence the conceptualisation of ADHD, public health policy implications and why it is unhelpful and incorrect to dichotomise genetic/biological and environmental explanations. It is essential that practitioners can interpret genetic and aetiological research findings and impart informed explanations to families.     

A Children of Twins Study of parental divorce and offspring psychopathology

BACKGROUND: Although parental divorce is associated with increased substance use and internalizing problems, experiencing the separation of one's parents may not cause these outcomes. The relations may be due to genetic or environmental selection factors, characteristics that lead to both marital separation and offspring functioning. METHOD: We used the Children of Twins (CoT) Design to explore whether unmeasured genetic or environmental factors related to the twin parent, and measured characteristics of both parents, account for the association between parental divorce and offspring substance use and internalizing problems. RESULTS: The association between parental divorce and offspring substance use problems remained robust when controlling for genetic and environmental risk from the twin parent associated with parental divorce, and measured characteristics of both parents. The results do not prove, but are consistent with, a causal connection. In contrast, the analyses suggest that shared genetic liability in parents and their offspring accounts for the increased risk of internalizing problems in adult offspring from divorced families. CONCLUSIONS: The study illustrates that unmeasured genetic and environmental selection factors must be considered when studying parental divorce. In explaining associations between parental divorce and young-adult adjustment, our evidence suggests that selection versus causal mechanisms may operate differently for substance abuse (a causal relation) and internalizing problems (an artifact of selection). The CoT design only controls for the genetic and environmental characteristics of one parent; thus, additional genetically informed analyses are needed.     

Unraveling the effect of genes and environment in the transmission of parental antisocial behavior to children's conduct disturbance, depression and hyperactivity

Background: A critical issue in devising effective interventions for the treatment of children’s behavioral and emotional problems identifying genuine family environmental factors that place children at risk. In most twin and family studies, environmental factors are confounded with both direct genetic risk from parents and the indirect effect of genes influencing parents’ ability to provide an optimal rearing environment. The present study was undertaken to determine whether parental psychopathology, specifically parental antisocial behavior (ASP), is a genuine environmental risk factor for juvenile conduct disturbance, depression and hyperactivity, or whether the association between parental ASP and children’s behavioral and emotional problems can be explained as a secondary consequence of the intergenerational transmission of genetic factors. Methods: An extended children of twins design comprised of data collected on 2,674 adult female and male twins, their spouses, and 2,454 of their children was used to test whether genetic and/or family environmental factors best accounted for the association between parental antisocial behavior and children’s behavioral problems. An age‐matched sample of 2,826 juvenile twin pairs from the Virginia Twin Study of Adolescent Behavioral Development was also included to examine developmental differences in gene expression by partitioning child‐specific transmissible effects from those effects that persist into adulthood. The fit of alternative models was evaluated using the statistical program Mx. Results: We found distinct patterns of transmission between parental antisocial behavior and juvenile conduct, depression and hyperactivity. Genetic and family environmental factors accounted for the resemblance between parents’ ASP and children’s conduct disturbance. Family environmental factors alone explained the association between child depression and parental ASP, and the impact of parental ASP on hyperactivity was entirely genetic. Conclusions: These findings underscore differences in the contribution of genetic and environmental factors on the patterns of association between parental antisocial behavior and juvenile psychopathology, having important clinical implications for the prevention and amelioration of child behavioral and emotional problems.     

Editorial: A double‐edged sword: advantages and disadvantages to the current emphasis on biogenetic causes of child psychopathology

Research on child psychopathology is a largely biogenetic endeavor these days, at least according to current funding priorities at the National Institutes of Health in the US. This heavy focus on genetic contributions to child psychopathology has some real advantages. Available research has conclusively indicated that child and adolescent mental health problems are partially genetic in origin and, moreover, are related to neural structure and function (as an example, see Plomin et al.). Moreover, these genetic effects may be responsible for some previously reported ‘environmental’ effects, such that, what appear to be direct environmental risk factors may in fact reflect genetic/familial risks. As one example, Sengupta et al. (this issue) found that maternal smoking during pregnancy was in fact a marker of maternal and paternal psychopathology. Put another way, the association between ADHD and maternal smoking during pregnancy may index a genetic/familial risk for a more severe form of ADHD, rather than a direct effect of uterine exposure to cigarettes. A final, more subtle reason for the current trend towards biogenetic research is that it has the rarely‐discussed but all‐too‐important ‘allure of the unknown’. We have only just recently been able to directly explore the biological underpinnings of psychopathology; and as technology advances, so too will the insights gained (presumably). This offers both funding agencies and individual scientists the very real possibility of making a major new discovery – a siren's call for most of us. In sharp contrast, decades of research have explored putatively environmental contributions to child and adolescent psychopathology. New paradigm‐shifting discoveries are thus likely to be fewer in number and farther between (if we continue using traditional study designs that omit joint consideration of biology, that is). In short, biogenetic research just feels more cutting edge at the moment. The clear merits of such work notwithstanding, there are a number of critical disadvantages to the current emphasis on genetics. These issues are presented below, not necessarily in order of importance.     

Research perspectives in the etiology of congenital anorectal malformations using data of the International Consortium on Anorectal Malformations: evidence for risk factors across different populations

Purpose

The recently established International Consortium on Anorectal Malformations aims to identify genetic and environmental risk factors in the etiology of syndromic and nonsyndromic anorectal malformations (ARM) by promoting collaboration through data sharing and combined research activities.

Methods

The consortium attempts to recruit at least 1,000 ARM cases. DNA samples are collected from case–parent triads to identify genetic factors involved in ARM. Several genetic techniques will be applied, including SNP arrays, gene and whole exome sequencing, and a genome-wide association study. Questionnaires inquiring about circumstances before and during pregnancy will be used to obtain environmental risk factor data.

Results

Currently, 701 ARM cases have been recruited throughout Europe. Clinical data are available from all cases, and DNA samples and questionnaire data mainly from the Dutch and German cases. Preliminary analyses on environmental risk factors in the Dutch and German cohort found associations between ARM and family history of ARM, fever during first trimester of pregnancy and maternal job exposure to cleaning agents and solvents.

Conclusion

First results show that both genetic and environmental factors may contribute to the multifactorial etiology of ARM. The International Consortium on Anorectal Malformations will provide possibilities to study and detect important genes and environmental risk factors for ARM, ultimately resulting in better genetic counseling, improved therapies, and primary prevention.     

The influence of growth on development outcome in extremely low birthweight infants at 2 years of age

OBJECTIVE: To determine if weight < 3rd and < 10th centile at 2 years in extremely low birthweight (ELBW) infants is associated with problems of development and motor skills, and whether this association is explained by perinatal risk status. METHODOLOGY: One hundred and ninety-eight of 226 (88%) surviving ELBW infants born between January 1987 and December 1992 were assessed at 2 years corrected age. Children were classified as being at low perinatal risk (n = 128) or high perinatal risk (n = 70) for adverse developmental outcome based on perinatal risk factors. Weight at 2 years was classified as < 3rd, 3rd-9th or > or = 10th centile for age and gender. Development was assessed using the Griffiths Mental Developmental Scales and motor skills using the Neurosensory Motor Developmental Assessment (NSMDA). RESULTS: For the total study group weight centile was strongly related to General Quotient (GQ) and motor abilities. For children < 3rd percentile (n = 48) mean (GQ) was 90.4 (SD, 15.9), for children between the 3rd-9th percentile (n = 49) 91.5 (SD, 17.9), and for children > or = 10th percentile (n = 99) mean GQ was 99.8 (SD, 8.6). The association with mean GQ and NSMDA category occurred for the high-risk subgroup and became non-significant in the low-risk subgroup if neurologically abnormal children were excluded. Other perinatal risk factors, exposure to breast milk, level of maternal education, marital status and history of feeding problems or infections over the 2 years did not confound this association. CONCLUSION: Low weight percentile at 2 years was related to adverse developmental outcome in ELBW infants at high perinatal risk or with neurological impairment, though minimal association was present for neurologically normal infants at low perinatal risk.     

I think, therefore I am: a twin study of attributional style in adolescents

BACKGROUND: Parenting factors may be important to the development of attributional style in adolescence, which in turn relates to depression symptoms. These relationships have mainly been considered in terms of social risk mechanisms, and little is known about the role of genetic influences. METHOD: Self-reported measures of attributional style, depression symptoms and parental disciplinary styles were administered to over 1300 adolescent twin and sibling pairs. Model-fitting techniques were used to examine the role of genetic and environmental influences. RESULTS: Moderate genetic influences on attributional style were demonstrated, and furthermore, its association with depression reflected considerable genetic effects. Familial factors were implicated in the association between attributional style and punitive parenting, although genetic from shared environmental causes could not be distinguished. CONCLUSIONS: Our results demonstrate that attributional style is influenced by genetic, as well as social factors. Implications for aetiological pathways integrating cognitive, genetic and social factors on adolescent depression are discussed.     

Genetic and environmental influences on the transmission of parental depression to children’s depression and conduct disturbance: an extended Children of Twins study

Background: Despite the increased risk of depression and conduct problems in children of depressed parents, the mechanism by which parental depression affects their children’s behavioral and emotional functioning is not well understood. The present study was undertaken to determine whether parental depression represents a genuine environmental risk factor in children’s psychopathology, or whether children’s depression/conduct can be explained as a secondary consequence of the genetic liability transmitted from parents to their offspring. Methods: Children of Twins (COT) data collected on 2,674 adult female and male twins, their spouses, and 2,940 of their children were used to address whether genetic and/or family environmental factors best account for the association between depression in parents and depression and conduct problems in their children. Data collected on juvenile twins from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) were also included to estimate child‐specific genetic and environmental influences apart from those effects arising from the transmission of the parental depression itself. The fit of alternative Children of Twin models were evaluated using the statistical program Mx. Results: The most compelling model for the association between parental and juvenile depression was a model of direct environmental risk. Both family environmental and genetic factors accounted for the association between parental depression and child conduct disturbance. Conclusions: These findings illustrate how a genetically mediated behavior such as parental depression can have both an environmental and genetic impact on children’s behavior. We find developmentally specific genetic factors underlying risk to juvenile and adult depression. A shared genetic liability influences both parental depression and juvenile conduct disturbance, implicating child conduct disturbance (CD) as an early indicator of genetic risk for depression in adulthood. In summary, our analyses demonstrate differences in the impact of parental depression on different forms of child psychopathology, and at various stages of development.     

Pre- and peri-natal environmental risks for attention-deficit hyperactivity disorder (ADHD): the potential role of epigenetic processes in mediating susceptibility

Attention-deficit hyperactivity disorder (ADHD) is a common childhood neurobehavioural disorder defined by symptoms of developmentally inappropriate inattention, impulsivity and hyperactivity. As is the norm for most psychiatric phenotypes, traditional aetiological studies have focused primarily on the interplay between genetic and environmental factors. It is likely that epigenetic factors, i.e., heritable, but reversible changes to genomic function that are independent of DNA sequence, are also important. It is known that epigenetic processes can be induced following exposure to a range of external factors, and thus provide a mechanism by which the environment can lead to long-term alterations in phenotype. In this article we hypothesise that epigenetic dysregulation may mediate the association observed between early-development environmental insults and ADHD. We propose that understanding the epigenetic processes involved in linking specific environmental pathogens to an increased risk for ADHD may offer new possibilities for preventative and therapeutic intervention.     

Perinatal testicular torsion in siblings

The management of perinatal torsion remains a controversial topic in pediatric urology. We present two cases of brothers diagnosed with perinatal torsion during the postnatal period. The first brother experienced bilateral torsion, with both testes found to be unsalvageable during emergent surgery on day 4 of life. Two years later the second brother was found on his newborn exam to have findings consistent with unilateral left testicular torsion. Emergent exploration was undertaken that confirmed the left testis to be necrotic. The contralateral testis was found to be normal and a fixation procedure was undertaken.     

Genetic association studies in VLBW infants exemplifying susceptibility to sepsis--recent findings and implications for future research

CONTEXT: In recent years, tremendous effort has been carried out to study the genetic basis of susceptibility to development, progression and severity of complex diseases and response to therapy. The ultimate goal of these investigations is to find new tools for prevention and treatment of these complex diseases, such as sepsis in very-low-birth-weight (VLBW) infants. VLBW cohorts have a restricted clinical risk profile for the development of sepsis including immaturity of immune functions and antenatal/perinatal risk factors but also a significant event rate of sepsis within a short period of observational time. Therefore, prospective VLBW cohorts are advantageous for the investigation of candidate genetic risk factors of sepsis compared to adult cohorts. Furthermore, environmental factors are much better documented and highly controlled for VLBW infants in a standardized NICU setting compared to adult cohorts which are influenced by a variety of environmental risk factors, e.g. habits and comorbidities. OBJECTIVE: The aim of this review is to discuss the value and limitations of genetic association studies in VLBW infant cohorts exemplifying recent findings for genetic susceptibility to neonatal sepsis. DATA SOURCE: Published Medline articles reporting on studies of associations between genetic polymorphisms, neonatal sepsis and septic shock in VLBW infants. CONCLUSIONS: Up-to-date, the classical approach to investigate the genetic component of susceptibility to sepsis in VLBW infants by means of twin and concordance studies has not been implemented yet. Regarding the interpretation of data from current genetic association studies, one should be aware of significant differences in cohort size, study design and definition of cases, controls and clinical end points. Furthermore, the contribution of genetic variants to susceptibility to sepsis may be specifically influenced by the immaturity of the immune response in VLBW infants, the selectivity of responsiveness to certain pathogens and the genotopyic/phenotypic variability of pathogens. We provide implications for the conduct and evaluation of future association studies with particular reference to methodological quality standards.     

The development of obesity in childhood

Multiple factors appear to influence and promote the development of obesity: The importance of genetic factors has been demonstrated in some studies, however, it is very difficult to distinguish between environmental and genetic influences. Independently, increased birthweight, massive weight gain in the first months after birth and overweight of the mother or of both parents seem to be risk factors, which are able to promote the development of childhood obesity. In the past few years more attention has been paid to psychological factors and their influence on appetite, physical activity and energy balance. Whether metabolic changes on cellular and microcellular basis can cause obesity is not sufficiently known until now. Nutrition in early childhood and fat cell hyperplasia and hypertrophia induced by nutritional factors probably do not imply persistence of obesity but may promote obesity and worsen the prognosis of therapy. Due to the fact that a high percentage of obese adolescents remain obese in adulthood, and due to the poor results in the treatment of obesity as well as the association of overweight with an increased risk for morbidity and mortality an effective therapy and prevention of obesity even during childhood seem to be of great importance.     

Cerebral palsy among children of immigrants in Denmark and the role of socioeconomic status

BackgroundChildren of immigrants in Denmark have excess risk for some of the most well-established risk factors for cerebral palsy (CP).ObjectivesTo study differences in risk of CP between children of immigrants and children of Danish-born mothers, and explore whether socioeconomic status drives any potential association.MethodsA register-based cohort study including 1,274,616 children born in Denmark between 1981 and 2007. Of these, 2807 had a validated CP diagnosis in the Danish CP Register. We estimated the risk of CP as odds ratios (OR) using logistic regression and assessed mediation through socioeconomic status using natural effect models.ResultsIn children of Danish-born mothers, 2.2/1000 had CP overall and the prevalence was similar for children of immigrants. However, children of immigrants had lower risk of unilateral spastic CP than children of Danish native-born mothers; OR = 0.59 (95% CI:0.38–0.91) for Western and OR = 0.79 (95% CI:0.61–1.03) for Non-Western immigrants. By contrast, the risk of bilateral spastic CP was higher in children of Non-Western immigrants (OR = 1.27 (95% CI:1.05–1.53)), especially from Turkey and Pakistan compared with children of Danish native-born mothers. The mediation analysis revealed an indirect effect (through maternal educational level and household income) with an OR of 1.06 (95% CI:0.99–1.14) for children of Non-Western immigrants.ConclusionsWhile children of immigrants had lower risk of unilateral spastic CP than children of Danish-born mothers, the risk of bilateral spastic CP was increased in children of Non-Western immigrants. Socioeconomic status did not appear to be a significant contributor to the increased risk of bilateral spastic CP.     

Is neonatal phototherapy associated with an increased risk for hospitalized childhood bronchial asthma?

This population-based register study examined if factors during the fetal and neonatal period influence the risk for the child to develop bronchial asthma (asthma). From the Swedish Hospital Discharge Register we identified children, born between 1987 and 1999, who had been hospitalized for asthma up to 2001. Thus, the outcome measure contains only hospitalized cases, not all children with asthma. Children younger than 2 yr at admission were excluded because of the uncertainty about the diagnosis of asthma in younger children. The remaining 14,803 children were compared with all children born the same years, recorded in the Swedish Medical Birth Registry, for information on pre- and perinatal characteristics. Odds ratios (ORs) were calculated with Mantel-Haenszel technique and 95% confidence intervals (CIs) with Miettinen's test-based method. The presence of various maternal and neonatal confounders were identified and adjusted for in the analyses. The association between some known factors and childhood asthma were confirmed: young maternal age, maternal smoking, period of unwanted childlessness, low maternal level of education, maternal diabetes, preterm birth, low birth weight, small-for-gestational age, caesarean section, and instrumental vaginal delivery. A number of neonatal characteristics were shown to be independent risk factors: sepsis or pneumonia, neonatal respiratory problems and treatments, neonatal icterus, and/or neonatal phototherapy. The association with icterus and phototherapy remained after exclusion of cases showing other neonatal risk factors and after adjustment for maternal factors (OR 1.27, 95% CI: 1.08-1.50), and increased to 1.5 if the children had been hospitalized for asthma more than once. In conclusion, our results suggest an association between neonatal icterus and/or treatment with neonatal phototherapy and hospitalized childhood asthma. This association needs further exploration.     

Absence of breast-feeding is associated with the risk of type 1 diabetes: a case–control study in a population with rapidly increasing incidence

There are indications that the effect of environmental factors on the risk of type 1 diabetes mellitus (T1DM) is increasing over time. This can be documented by the rapid increase of T1DM incidence in genetically stable populations. Our aim was to study an association of T1DM with the variable factors of the perinatal period and of early infancy, using data from children born over a period of changing exposure to some of the studied factors. A case–control dataset was analysed, consisting of 868 diabetic children and 1,466 anonymous controls, mostly schoolmates of the children with T1DM. The data were collected using structured questionnaires completed by parents. After performing univariate analyses, the associations were analysed using multiple logistic regression adjusted for potential confounders, including the year of birth. The risk of T1DM decreased with increasing duration of breast-feeding, while no breast-feeding was associated with an increased T1DM risk, OR=1.93 [95% CI: 1.33–2.80], breast-feeding for more than 12 months was protective, OR=0.42 [95% CI: 0.22–0.81], both being relative to the reference category of breast-feeding for 1–3 months. A short duration of day-care attendance (none or less than 1 year) was weakly associated with the risk of T1DM, OR=1.65 [95% CI: 1.05–2.62]. No association was detected between T1DM and signs of prenatal infections, perinatal stress factors, birth size and weight, indicators of crowding or the presence of a domestic pet in the household. Short breast-feeding period and short attendance to day care is associated with the risk of T1DM in Czech children.     

Health promotion for children,mothers and families: here’s why we should “think about it before conception”

About 90,000 preterm infants or babies with birth defects are born in Italy every year, nearly 250 per day. These congenital conditions and their outcomes represent the most important burden of disease affecting the health status and the quality of life during infancy, childhood and beyond. In many cases they are fostered by the presence of maternal and/or paternal preconception risk factors whose effects can be modified by primary prevention.In the contemporary vision of maternal and child health, the traditional gap between preconception period and pregnancy is overcome through promotion of reproductive health and wellness in women, men and couples, regardless of their reproductive plans and possible future pregnancies. This paradigm should become the basic foundation to improve and protect infants’, children’s and adolescents’ health. Useful interventions belong to four broad areas: a) promotion of women’s and couples’ health in general, and protection from risk of adverse events in future pregnancies (if any); b) identification and treatment of conditions that increase the risk of adverse reproductive outcomes; c) help for women (couples) planning for pregnancy; d) identification of genetic risks, and help for independent and responsible decision making.Pediatricians and neonatologists can effectively promote primary prevention in the interconception period, when parents seek consultation for their previous child, in adolescent medicine, in family health education, in socio-sanitary network, and in advocacy activities in favor of infants and children. These actions should be part of an operational framework including perinatal outreach programs, information campaigns, and focus on problems of high-risk women, children and families.     

Laterality of acute otitis media: different clinical and microbiologic characteristics

BACKGROUND: A large individual patient data meta-analysis recently showed that children aged less than 2 years with bilateral, as compared with unilateral, acute otitis media (AOM) were at higher risk for persistent symptoms without antibiotic treatment. Prior studies have shown a propensity for children with bilateral AOM to be infected with bacterial pathogens, specifically Haemophilus influenzae. The objectives of this study were to further characterize risk factors for bilateral AOM and to assess the propensity for specific viral and bacterial pathogens to predispose to bilateral versus unilateral AOM. METHODS: We performed a secondary data analysis on 1216 cases of AOM diagnosed and treated at our institution: 566 subjects underwent tympanocentesis and middle ear fluid (MEF) culture. We compared subjects with bilateral and unilateral AOM for demographic characteristics, clinical findings, parent/clinician perception of AOM severity, and MEF study results for bacteria and viruses. RESULTS: When compared with children who have unilateral AOM, children with bilateral AOM were more likely to be younger (P < 0.001), have H. influenzae isolated from one or both MEFs (P < 0.0001), and have more severe inflammation of the tympanic membrane on otoscopic examination (P < 0.0001). CONCLUSION: Compared with children who have unilateral AOM, children with bilateral AOM are more likely to have bacteria in the MEF and have more severe inflammation of the tympanic membrane. This may help explain why children with bilateral AOM are more likely to experience persistent symptoms without antibiotic treatment. Laterality of AOM should be considered when discussing treatment options with parents.     

Congenital fusion of the jaws

Congenital fusion of the jaws is quite rare. It may be unilateral or bilateral, and involves only the soft tissues or both the hard and soft tissues. This anomaly may be seen separately or in association with syndromes. Maxillomandibular fusion restricts mouth opening causing problems in feeding, swallowing, and respiration. This condition can be easily treated. However, in long-standing cases, growth anomalies from TMJ ankylosis may occur.     

Transient neonatal hyperinsulinemic hypoglycemia and neurological outcome: a case report

Transient neonatal hyperinsulinemic hypoglycemia (TNHI) is a form of neonatal-onset hyperinsulinism which usually resolves completely in a few days or months. It is secondary to conditions such as maternal diabetes mellitus or intra-uterine growth retardation. Other rare causes of TNHI are perinatal asphyxia and gestational diabetes. Hyperinsulinemic hypoglycemia (HI) is also observed in association with rare metabolic or genetic conditions. It can also occur in newborns without risk factors. TNHI is usually a transient phenomenon. However, some newborns can have prolonged HI that requires treatment with diazoxide, persists for several months and then resolves spontaneously. Neonatal hyperinsulinemic hypoglycemia must be promptly and correctly diagnosed and treated in order to avoid neurological consequences. We describe a case of transient neonatal hyperinsulinemic hypoglycemia in a full-term born without perinatal complications and appropriate for gestational age with an unfavourable neurological outcome.     

The amount of brainstem gliosis in sudden infant death syndrome (SIDS) victims correlates with maternal cigarette smoking during pregnancy

Brainstem gliosis is elevated in some SIDS victims and has been associated with hypoxic-ischaemic events. Factors which increase the risk of SIDS include possible risk factors for hypoxic-ischaemic events during foetal and perinatal life. In this study a scoring system was developed whereby possible risk factors for hypoxic-ischaemic events during pregnancy, birth and in the perinatal period were correlated with the level of gliosis in the nucleus olivaris inferior in SIDS victims (n = 19). The mothers' antenatal care and obstetric records and the SIDS infants' perinatal hospital records were investigated, and each possible risk factor for hypoxic-ischaemic events was given one point. The points were summarized for each infant, and this sum was correlated with the level of gliosis in the infant's nucleus olivaris inferior. The number of cigarettes the mothers smoked during pregnancy was also compared with the level of gliosis. Our results show that in SIDS victims there is 41% probability that the more the mothers smoked during pregnancy, the more gliosis in the nucleus olivaris inferior is found in their infants (p < 0.01). Gliosis in the nucleus olivaris inferior also correlated with the possible risk factors for hypoxic-ischaemic events during pregnancy, birth and the perinatal period (r2 = 0.28, p < 0.05). However, if cigarette smoking was excluded as a possible hypoxic-ischaemic risk factor, no correlation was found.