Maxine Croft

Intellectual disability and other neuropsychiatric outcomes in high-risk children of mothers with schizophrenia, bipolar disorder and unipolar major depression

BACKGROUND Recent evidence points to partially shared genetics of neuropsychiatric disorders. AIMS We examined risk of intellectual disability and other neuropsychiatric outcomes in 3174 children of mothers with schizophrenia, bipolar disorder or unipolar major depression compared with 3129 children of unaffected mothers. METHOD We used record linkage across Western Australian population-based registers. The contribution of obstetric factors to risk of intellectual disability was assessed. RESULTS Children were at significantly increased risk of intellectual disability with odds ratios (ORs) of 3.2 (95% CI 1.8-5.7), 3.1 (95% CI 1.9-4.9) and 2.9 (95% CI 1.8-4.7) in the maternal schizophrenia, bipolar disorder and unipolar depression groups respectively. Multivariate analysis suggests familial and obstetric factors may contribute independently to the risk. Although summated labour/delivery complications (OR = 1.4, 95% CI 1.0-2.0) just failed to reach significance, neonatal encephalopathy (OR = 7.7, 95% CI 3.0-20.2) and fetal distress (OR = 1.8, 95% CI 1.1-2.7) were independent significant predictors. Rates of rare syndromes in children of mothers with mental disorder were well above population rates. Risk of pervasive developmental disorders, including autism, was significantly elevated for children of mothers with bipolar disorder. Risk of epilepsy was doubled for children of mothers with unipolar depression. CONCLUSIONS Our findings provide epidemiological support for clustering of neuropsychiatric disorders. Further larger epidemiological studies are warranted.

Cohort Profile: Pathways of risk from conception to disease: the Western Australian schizophrenia high-risk e-Cohort

Schizophrenia is a severely disabling disorder with a lifetime risk of 1% and a point prevalence of about 5 per 1000. Schizophrenia accounts for 2.3% of the global burden of disease. The aetiology of schizophrenia is complex. While there appears to be a significant genetic contribution, it is possible that many genes of small effect contribute to the disorder and that environmental risk factors interact with the genetic susceptibility. The impact of environmental risks appears to be complex, with no single environmental risk factor of major effect isolated to date. Putative candidate exposures include winter/spring season of birth, pregnancy and birth complications; prenatal starvation; urbanicity; migration and ethnicity, with the incidence apparently higher in second-generation migrants; stress and cannabis use. There have also been reports of possible age-related germ-line mutations such as those associated with older fathers. Much of the research into environmental risk factors has focused on the role of obstetric complications. While the level of reported risk associated with obstetric complications varies, Geddes and Lawrie, in a meta-analysis of published research, reported a pooled odds ratio of 2, a figure corroborated a few years later by Cannon et al., who calculated the individual odds ratio of 2 and under for the majority of the many complications that they reviewed. It appears that changes in the uterine environment such as increased maternal cytokines in response to hypoxia or infection, and stress-induced elevation of circulating corticosteroid levels may predispose some infants to psychopathology. In particular, much attention has been focused on hypoxic/ischemic events associated with and/or resulting in placentation abnormalities leading to fetal growth retardation and neonatal encephalopathy. In order to examine the role of genes, environment and their interaction in the expression of schizophrenia, a number of studies have adopted a prospective, longitudinal approach focusing on so-called ‘strategic’ populations of ‘high-risk’ children. These are children who are at genetically increased risk of developing schizophrenia because they have at least one parent with the disease and are therefore a priori enriched for predisposing genes. High-risk samples offer researchers the opportunity to address efficiently and parsimoniously key questions about risk factors and vulnerability. By parcelling out the separate contribution of genetic liability and environmental exposures, their relative contribution to the onset of schizophrenia and other neuropsychiatric outcomes can be assessed. One of the earliest of the longitudinal investigations of developmental pathways in the children of parents with schizophrenia was initiated by Barbara Fish in the early 1950s. Fish proposed that developmental retardation and neurological soft signs observed amongst the high-risk children in her sample were early markers of an inherited neurointegrative defect in schizophrenia which she named ‘pandysmaturation’. Dr Fish’s seminal work on pandysmaturation laid the groundwork for the formulation of the neurodevelopmental hypothesis of schizophrenia in the late 1980s. In its simplest form, the hypothesis states that critical circuits in the brain are affected by subtle disease processes in early development, with full-blown consequences Published by Oxford University Press on behalf of the International Epidemiological Association

The Western Australian register of childhood multiples: Effects of questionnaire design and follow-up protocol on response rates and representativeness

Twin registers have been established worldwide to study the roles of genes and the environment in health and behaviour. While questionnaire surveys are thought to be the most cost-effective way of collecting large amounts of data, low response rates can result in response bias. Many different strategies have been proposed to maximise response rates. A register of all multiple births occurring in Western Australia (WA) from 1980 onwards has been established using probabilistic record linkage techniques. Families who had not experienced the death of one or more of their multiples were invited to participate in the Western Australian Twin Child Health (WATCH) study, which studied the genetic and environmental determinants of childhood asthma and atopy. Several questionnaire designs and follow-up methods were assessed. We have shown that it was feasible to use a population-based register of multiple births to contact families for a questionnaire study. Questionnaire length, mode of follow-up, the number of responses required and the of participants all seemed to affect response.

Recorded pregnancy histories of the mothers of singletons and the mothers of twins: a longitudinal comparison.

A population-based record linkage case cohort of 239,995 births, to 119,214 women, born in Western Australia from 1980 to 2001 inclusive, was used to measure the recording of selected indicators of maternal health (current and prior) during pregnancy. We compared records of women with singleton pregnancies with that in twin pregnancies Mothers of first- and second-born singletons (n = 117,647) were compared with women with a first-born singleton followed by twins (n = 1,567). Binary indicators were used to calculate population prevalence of medical conditions, pregnancy complications and birth outcomes. Infant outcomes included stillbirth, low birthweight, preterm birth and birth defects. Women with twins were significantly older and taller, with similar rates of medical conditions and pregnancy complications during first singleton pregnancies compared with women with two consecutive singletons. However, during their second pregnancy, women with twins had significantly higher rates of essential hypertension, pre-eclampsia, threatened abortion, premature rupture of the membranes and ante partum hemorrhage with abruption than women with singletons. For both groups, maternal conditions in the first pregnancy were underreported in the second pregnancy, including diabetes, epilepsy, asthma, chronic renal dysfunction and essential hypertension. At the second birth, twins were 3 times more likely to be stillborn, 17 times more likely to be low birthweight and 4 times more likely to be delivered preterm compared with singletons. This research demonstrates the importance for epidemiologists and others, of having access to a complete maternal medical history for analyses of risks associated with maternal, infant and childhood morbidity.

The National Perinatal Depression Initiative: an evaluation of access to general practitioners, psychologists and psychiatrists through the Medicare Benefits Schedule

Objective: To evaluate the impact of the National Perinatal Depression Initiative on access to Medicare services for women at risk of perinatal mental illness. Method: Retrospective cohort study using difference-in-difference analytical methods to quantify the impact of the National Perinatal Depression Initiative policies on Medicare Benefits Schedule mental health usage by Australian women giving birth between 2006 and 2010. A random sample of women of reproductive age enrolled in Medicare who had not given birth where used as controls. The main outcome measures were the proportions of women giving birth each month who accessed a Medicare Benefits Schedule mental health items during the perinatal period (pregnancy through to the end of the first postnatal year) before and after the introduction of the National Perinatal Depression Initiative. Results: The proportion of women giving birth who accessed at least one mental health item during the perinatal period increased from 88 to 141 per 1000 between 2007 and 2010. The difference-in-difference analysis showed that while there was an overall increase in Medicare Benefits Schedule mental health item access as a result of the National Perinatal Depression Initiative, this did not reach statistical significance. However, the National Perinatal Depression Initiative was found to significantly increase access in subpopulations of women, particularly those aged under 25 and over 34 years living in major cities. Conclusion: In the 2 years following its introduction, the National Perinatal Depression Initiative was found to have increased access to Medicare funded mental health services in particular groups of women. However, an overall increase across all groups did not reach statistical significance. Further studies are needed to assess the impact of the National Perinatal Depression Initiative on women during childbearing years, including access to tertiary care, the cost-effectiveness of the initiative, and mental health outcomes. It is recommended that new mental health policy initiatives incorporate a planned strategic approach to evaluation, which includes sufficient follow-up to assess the impact of public health strategies.

The offspring of women with severe mental disorder

Schizophrenia is a severely disabling disorder with a lifetime risk of about 1%. The aetiology of schizophrenia is complex. Evidence from twin, adoptive and family studies indicates that the disorder involves a significant genetic contribution: children of women with schizophrenia have an 8- to 10-fold higher risk of developing the disorder compared with the general population [1], with the risk in a monozygotic co-twin increased to about 50-fold [2]. The pattern of inheritance in schizophrenia is not a simple Mendelian one. It is likely that multiple genes of small to moderate effect contribute to the disorder, and that environmental risk factors interact with this genetic susceptibility. However, the precise nature of the genetic and environmental risk factors remains unclear. It has long been suspected that disruptions to early brain development may be associated with an increased risk of adult-onset schizophrenia [3]. In the 1980s, these speculations became more clearly articulated under the generic label of the ‘neurodevelopmental hypothesis’ of schizophrenia [4]. It was proposed that critical circuits in the brain were affected in early development by a disease process, with full-blown consequences evident many years later in adolescence or early adulthood as schizophrenia [5]. The original theory is open as to whether the ‘disease process’ affecting neuronal development is genetically or environmentally determined. There are a number of indicators of neurodevelopmental disruption in schizophrenia including: (a) an increased risk of schizophrenia following obstetric complications at birth with good evidence that the risk is increased 2- to 7-fold [6]; (b) a history of neurointegrative defect in children who later develop schizophrenia [7], and (c) an increased frequency of minor physical anomalies [8] and neurological soft signs [9] in affected

The Western Australian Register of Childhood Multiples

Twin registers have been established worldwide to study the roles of genes and the environment in health and behaviour. While questionnaire surveys are thought to be the most cost-effective way of collecting large amounts of data, low response rates can result in response bias. Many different strategies have been proposed to maximise response rates. A register of all multiple births occurring in Western Australia (WA) from 1980 onwards has been established using probabilistic record linkage techniques. Families who had not experienced the death of one or more of their multiples were invited to participate in the Western Australian Twin Child Health (WATCH) study, which studied the genetic and environmental determinants of childhood asthma and atopy. Several questionnaire designs and follow-up methods were assessed. We have shown that it was feasible to use a population-based register of multiple births to contact families for a questionnaire study. Questionnaire length, mode of follow-up, the number of responses required and the of participants all seemed to affect response.

THE HIGH RISK CHILDREN OF MOTHERS WITH SCHIZOPHRENIA AND OTHER SEVERE MENTAL ILLNESS: DOES A MOTHER'S MENTAL ILLNESS INCREASE THE RISK OF SUDDEN INFANT DEATH SYNDROME?

psychosis following traumatic brain injury or allowed calculation of prevalence rates from data provided in the paper. We did computerassisted searches, scanned reference lists, searched journals and correspondedwith authorswherenecessary.We includedcase-control studies, cohort studies and family studies. Estimates of prevalence of psychosis from different studies were combined using fixed or random-effects meta-analysis, as appropropriate, with the data presented in forest plots. Heterogeneity among studies was estimated. Results: Our literature search and search of reference lists yielded 10015 references. The search was then limited to humans, which resulted in 9131 studies. Of these, 162 were considered to be potentially relevant. We excluded 154 studies, which did not meet inclusion criteria. We identified 8 studies which met our inclusion criteria, of which two were family studies, two were nested casecontrol studies and four were cohort studies. The overall pooled data revealed a significant association between TBI and subsequent psychosis (adjusted odds ratio=1.15, 1.04-1.26). However there was significant heterogeneity between the studies (Heterogeneity x=30.70 (d.f.=7) p=0.000; I=77.2%). Therefore,we decided to examine the family studies and case-control/cohort studies separately. Overall pooled data from the 6 population-based cohort and case-control studies showed an increased risk of development of schizophrenia or psychotic disorder in individuals who had been exposed to TBI (adjusted odds ratio=1.1, 1.005-1.231). However there was significant heterogeneity between the studies (Heterogeneity x=26.43 (d.f.=5); p<0.000; I=81.1%). Pooled data from the two family studies show an increased risk of schizophrenia after TBI in individuals who have a family history of schizophrenia (adjusted odds ratio=1.43, 1.14-1.8). There was no significant heterogeneity between the two studies. We were not able to examine the influence of location or age at onset of head injury. Discussion: We report an increased risk of psychosis following TBI. The increase among the general population is small about 10%but the risk ismore substantial among individualswhohave a family historyof schizophrenia or psychosis – about 43% increased risk. In particular, our findings point to the importance of gene-environment interaction in the etiology of psychosis following traumatic brain injury. Acknowledgements: Thisworkwas supportedbya Clinician Scientist Award to M. Cannon from the Health Research Board (Ireland).

The Western Australian Register of Childhood Multiples: Effects of Questionnaire Design and Follow-up Protocol on Response Rates and Representativeness

Twin registers have been established worldwide to study the roles of genes and the environment in health and behaviour. While questionnaire surveys are thought to be the most cost-effective way of collecting large amounts of data, low response rates can result in response bias. Many different strategies have been proposed to maximise response rates. A register of all multiple births occurring in Western Australia (WA) from 1980 onwards has been established using probabilistic record linkage techniques. Families who had not experienced the death of one or more of their multiples were invited to participate in the Western Australian Twin Child Health (WATCH) study, which studied the genetic and environmental determinants of childhood asthma and atopy. Several questionnaire designs and follow-up methods were assessed. We have shown that it was feasible to use a population-based register of multiple births to contact families for a questionnaire study. Questionnaire length, mode of follow-up, the number of responses required and the of participants all seemed to affect response.