Introducing the ORIGINS project: a community-based interventional birth cohort.

Objectives Non-communicable diseases (NCDs) pose the greatest threat to human health globally. The dramatic rise in early onset NCDs - such as childhood obesity, the allergy epidemic and an increasing burden of mental ill health in children and youth - reflect the profound early impact of modern environments on developing systems. The ORIGINS Project is a research platform enabling world class investigation of early antecedent pathways to NCDs, and how to curtail these. As well as facilitating strategic long-term research capacity, ORIGINS is a pipeline for short-term productivity through a series of clinical trials, early interventions, mechanistic studies, and targeted research questions to improve maternal and paternal health and the early environment. Methods ORIGINS is a decade-long collaborative initiative between the Joondalup Health Campus (JHC) and the Telethon Kids Institute (TKI) to establish a Western Australian (WA) birth cohort of 10,000 families, enrolled during pregnancy. It is currently funded to follow up participating children and their families to five years of age. Comprehensive data and biological samples are collected from participants at up to 15 different timepoints, from the first antenatal clinic visit. In the process, ORIGINS is creating a major research platform, consisting of an extensive, world class biobank and databank. Of key strength and novelty, ORIGINS includes a series of harmonised nested sub-projects integrated with clinical and diagnostic services and providing real-time feedback to improve the health of individuals and the community. Conclusions At its core, ORIGINS aims to improve the health and quality of life of the next generation through improved pathways to optimise the early environment and reduce adversity by promoting primary prevention, early detection and early intervention. This dynamic, interactive, community-based project not only provides novel research capacity, productivity, collaboration and translational impact on future generations - it is also anticipated to have flow on benefits for community engagement, cohesion and purpose. This will provide a sentinel example for tailored replication in other communities around the world as part of interconnected grass root strategies to improve planetary health.

Literacy and Numeracy Underachievement in Boys and Girls With ADHD.

Objective: The aim was to determine literacy and numeracy outcomes, among children with and without ADHD by gestational age and gender. Method: De-identified linked population data from the Western Australian Monitoring of Drugs of Dependence System and Western Australian Literacy and Numeracy Assessment databases, and the Midwives Notification System used information on 6,819 children with ADHD compared with 14,451 non-ADHD children. Results: A total of 23% of boys and 28% of girls with ADHD had numeracy scores below the benchmark in School Year 3, compared with 11% of children without ADHD. These differences were also evident for reading, writing, and spelling through primary school. Children with ADHD and reduced gestational age were at a greater risk of not meeting numeracy and reading benchmarks, compared with children born at term. Conclusion: Children with ADHD are disadvantaged from an early age in key areas of learning, and this risk increased with reduction in gestational age at birth.

Literacy and Numeracy Underachievement in Boys and Girls With ADHD.

Objective: To determine literacy and numeracy outcomes, among children with and without ADHD by gestational age and gender. Method: De-identified linked population data from the Western Australian Monitoring of Drug Dependence Systems, Western Australian Literacy and Numeracy Assessment database, and the Midwives Notification System used information on 6,819 children with ADHD compared with 14,451 non-ADHD children. Results: Twenty-three percent of boys and 28% of girls with ADHD had numeracy scores below the benchmark in School Year 3, compared with 11% of children without ADHD. These differences were also evident in reading, writing, and spelling through primary school. Children with ADHD and reduced gestational age were at a greater risk of not meeting numeracy and reading benchmarks, compared with children born at term. Conclusion: Children with ADHD are disadvantaged from an early age in key areas of learning, and this risk increased with reduction in gestational age at birth.

Children diagnosed with attention deficit disorder and their hospitalisations: population data linkage study.

Examine the hospital admission risk in young children who are subsequently diagnosed with attention deficit hyperactivity disorder (ADHD). We conducted a population-based, record linkage study. Records of all non-Aboriginal children under 18 years who met the DSMIV/ICD10 criteria for ADHD and prescribed stimulant medication in Western Australia between 2003 and 2007 (n = 11,902) were linked to two other health data systems-the hospital morbidity data system and the midwives notification system (MNS). The non-ADHD reference population (n = 27,304) was randomly selected from the MNS. Compared with controls, children under 4 years who subsequently were diagnosed and treated for ADHD were 70% [odds ratio (OR) 1.70; 95% confidence intervals (CI) 1.62-1.77] more likely to be admitted to hospital under 4 years of age. There was an increased risk for injury or poison (OR 1.73; 95% CI 1.59-1.88), respiratory disease (OR 1.49; 95% CI 1.40-1.59), ear disease (OR 2.03; 95% CI 1.86-2.21), infectious diseases (OR 1.68; 95% CI 1.53-1.85) and neurological conditions (OR 2.03; 95% CI 1.68-2.44). Admissions under 4 years of age for head injuries, burns, poisons, all other injuries, diseases of the tonsils and adenoids, asthma and early infections were all more common amongst children subsequently diagnosed with and treated for ADHD. There is significant early hospital morbidity for children subsequently diagnosed with ADHD. Multiple aetiologies and causal pathways need to be considered where some of these may include early infections, inflammatory conditions, epilepsy and injuries. Future studies should look at which of these conditions may be on the causal pathway or likely early markers for ADHD.

Contact with the juvenile justice system in children treated with stimulant medication for attention deficit hyperactivity disorder: a population study.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is the most frequent neurodevelopmental disorder in children and is sometimes noted retrospectively in young people and adults who are incarcerated. We aimed to investigate juvenile justice encounters in children with and without ADHD. METHODS: Between January, 1995, and December, 2010, we did a population-based cohort study in Western Australia. Anonymised linked population data were obtained from the Western Australia Midwives Notification System. 12 831 non-Indigenous Australian children and young people aged 10-21 years, who were diagnosed and treated with stimulant drugs for ADHD and had a record in the Monitoring Drugs of Dependence System (ADHD cohort), were identified and frequency-matched by age, sex, and socioeconomic status to 29 722 non-Indigenous Australian children and young people who had no record in the Monitoring Drugs of Dependence System (controls). Community correction records and incarceration records were retrieved for all participants from Total Offending Management Solutions. Our primary outcome was to compare justice outcomes between children with ADHD and those without this disorder. We compared cohorts by conditional logistic regression analysis. FINDINGS: 9939 boys and 2892 girls were diagnosed and treated for ADHD; 22 875 boys and 6847 girls were frequency-matched controls. 792 (8%) boys and 75 (3%) girls with ADHD had a community correction record, compared with 822 (4%) boys and 75 (1%) girls without ADHD. 132 (1%) boys and 11 (<1%) girls with ADHD had an incarceration record, compared with 108 (<1%) boys and five (<1%) girls without ADHD. Compared with controls, boys with ADHD were two and half times more likely to have a community correction record (odds ratio 2·48, 95% CI 2·22-2·76) or an incarceration record (2·63, 2·01-3·44). Compared with their non-ADHD counterparts, girls with ADHD were nearly three times more likely to have a community correction record (odds ratio 2·86, 95% CI 2·03-4·03) and seven times more likely to have an incarceration record (7·27, 2·29-23·08). Boys with ADHD received their first community correction record at a younger age compared with controls (15·9 vs 16·3 years; p=0·0005), but age at first community correction record was similar for girls (16·5 vs 16·4 years; p=0·87). Burglaries and breaking and entering were the most common reason for a first justice record (total 659 [37%]), and this offence was twice as likely in children with ADHD (for boys, odds ratio 2·24, 95% CI 1·90-2·64; for girls, 2·19, 1·40-3·42). INTERPRETATION: Justice outcomes for boys and girls were more frequent among children and young people treated for ADHD compared with their non-ADHD counterparts. Unlike girls, boys were more likely to offend at a younger age. Early diagnosis and management of children and young people with ADHD might reduce the over-representation of children with this disorder within the juvenile justice system. FUNDING: National Health and Medical Research Council (Australia), Australian Research Council.

Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder.

BACKGROUND: Early environmental risk factors associated with attention-deficit/hyperactivity disorder (ADHD) have been increasingly suggested. Our study investigates the maternal, pregnancy, and newborn risk factors by gender for children prescribed stimulant medication for treatment of ADHD in Western Australia. METHODS: This is a population-based, record linkage case-control study. The records of all non-Aboriginal children and adolescents born in Western Australia and aged <25 years who were diagnosed with ADHD and prescribed stimulant medication (cases = 12,991) were linked to the Midwives Notification System (MNS) to obtain maternal, pregnancy, and birth information. The control population of 30,071 children was randomly selected from the MNS. RESULTS: Mothers of children with ADHD were significantly more likely to be younger, be single, have smoked in pregnancy, have labor induced, and experience threatened preterm labor, preeclampsia, urinary tract infection in pregnancy, or early term delivery irrespective of the gender of the child, compared with the control group. In the fully adjusted model, a novel finding was of a possible protective effect of oxytocin augmentation in girls. Low birth weight, postterm pregnancy, small for gestational age infant, fetal distress, and low Apgar scores were not identified as risk factors. CONCLUSIONS: Smoking in pregnancy, maternal urinary tract infection, being induced, and experiencing threatened preterm labor increase the risk of ADHD, with little gender difference, although oxytocin augmentation of labor appears protective for girls. Early term deliveries marginally increased the risk of ADHD. Studies designed to disentangle possible mechanisms, confounders, or moderators of these risk factors are warranted.

Are women with major depression in pregnancy identifiable in population health data?

BACKGROUND: Although record linkage of routinely collected health datasets is a valuable research resource, most datasets are established for administrative purposes and not for health outcomes research. In order for meaningful results to be extrapolated to specific populations, the limitations of the data and linkage methodology need to be investigated and clarified. It is the objective of this study to investigate the differences in ascertainment which may arise between a hospital admission dataset and a dispensing claims dataset, using major depression in pregnancy as an example. The safe use of antidepressants in pregnancy is an ongoing issue for clinicians with around 10% of pregnant women suffer from depression. As the birth admission will be the first admission to hospital during their pregnancy for most women, their use of antidepressants, or their depressive condition, may not be revealed to the attending hospital clinicians. This may result in adverse outcomes for the mother and infant. METHODS: Population-based de-identified data were provided from the Western Australian Data Linkage System linking the administrative health records of women with a delivery to related records from the Midwives' Notification System, the Hospital Morbidity Data System and the national Pharmaceutical Benefits Scheme dataset. The women with depression during their pregnancy were ascertained in two ways: women with dispensing records relating to dispensed antidepressant medicines with an WHO ATC code to the 3rd level, pharmacological subgroup, 'N06A Antidepressants'; and, women with any hospital admission during pregnancy, including the birth admission, if a comorbidity was recorded relating to depression. RESULTS: From 2002 to 2005, there were 96698 births in WA. At least one antidepressant was dispensed to 4485 (4.6%) pregnant women. There were 3010 (3.1%) women with a comorbidity related to depression recorded on their delivery admission, or other admission to hospital during pregnancy. There were a total of 7495 pregnancies identified by either set of records. Using data linkage, we determined that these records represented 6596 individual pregnancies. Only 899 pregnancies were found in both groups (13.6% of all cases). 80% of women dispensed an antidepressant did not have depression recorded as a comorbidity on their hospital records. A simple capture-recapture calculation suggests the prevalence of depression in this population of pregnant women to be around 16%. CONCLUSION: No single data source is likely to provide a complete health profile for an individual. For women with depression in pregnancy and dispensed antidepressants, the hospital admission data do not adequately capture all cases.

Off-label use of ondansetron in pregnancy in Western Australia.

AIMS: Nausea and vomiting of pregnancy is the most common medical condition in pregnancy. There is an increasing trend to prescribe ondansetron although its safety for use in pregnancy has not been established. METHODS: Exposed pregnancies were all births in Western Australia, 2002-2005, where the mother was dispensed ondansetron under the Australian Pharmaceutical Benefits Scheme, compared with all other births during the same period. Outcomes investigated include maternal and child characteristics, birth defects, pregnancy, and delivery characteristics. RESULTS: There were 96,968 births from 2002 to 2005. Ondansetron was dispensed to 251 pregnant women during this period. The women dispensed ondansetron were more likely to be privately insured (OR: 5.8; 95% CI: 4.3-7.9), to be Caucasian (3.3; 1.9-5.7), not to smoke during their pregnancy (2.9; 1.8-4.7), to have a multiple birth (2.7; 1.5-5.0), and to have used fertility treatment (1.8; 1.0-3.4). There was a small but not significantly increased risk of a major birth defect with first trimester exposure (1.2; 0.6-2.2). CONCLUSIONS: Our study did not detect any adverse outcomes from the use of ondansetron in pregnancy but could not conclude that ondansetron is safe to use in pregnancy.

Early morbidity and mortality following in utero exposure to selective serotonin reuptake inhibitors: a population-based study in Western Australia.

BACKGROUND: The early years of life have a profound effect on a child's developmental pathway. The children born to mothers suffering from depression may be at risk of increased morbidity and mortality in the first years of life. OBJECTIVE: The objective of this study was to investigate the hospital admissions and mortality of children whose mothers were dispensed a selective serotonin reuptake inhibitor (SSRI) during their pregnancy. METHODS: This was a population-based study of all pregnancy events in Western Australia (WA) from 2002 to 2005. The study used linkable state health administrative data from the WA Data Linkage System (WADLS) and the national Pharmaceutical Benefits Scheme (PBS), enabling birth outcomes, hospital admissions and deaths to be ascertained for the children of women dispensed an SSRI during their pregnancy. RESULTS: There were 3764 children born to 3703 women who had been dispensed an SSRI during their pregnancy (3.8% of all pregnancies in WA, 2002-5), and 94 561 children born to 92 995 women who had not been dispensed an SSRI. Mean birth weight, length and APGAR score at 5 minutes were significantly lower in children of women dispensed an SSRI, regardless of whether the SSRI was dispensed in trimester 1, or, trimester 2 or 3 only. 0.9% of the live born children in the SSRI group had died before the age of 1 year compared with 0.5% of the non-SSRI group (odds ratio [OR] 1.8; 95% CI 1.3, 2.6). Before the age of 2 years, 42.9% of the children in the SSRI group had been admitted to hospital after their birth admission, compared with 34.1% of the non-SSRI group (OR 1.4; 95% CI 1.3, 1.6). The most common reason for admission to hospital was acute bronchiolitis (OR 1.6; 95% CI 1.3, 1.8), with an increased risk seen in children of mothers who did not smoke during their pregnancy (OR 1.7; 95% CI 1.4, 2.0). CONCLUSIONS: The children in the SSRI group were more likely to be admitted to hospital in the first years of life, and this may reflect their prenatal exposure to SSRIs, be related to maternal depression, or SSRI use may be a proxy for an environmental exposure such as smoking, or a combination of these factors. Although the numbers of deaths in the first year of life were small, the increased risk of death in the first year of life in the SSRI group (OR 1.8; 95% CI 1.3, 2.6) is a new finding and should be investigated further.

Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy.

BACKGROUND: The safety of selective serotonin reuptake inhibitors (SSRIs) during pregnancy remains uncertain. The purpose of this study was to investigate dispensing patterns and pregnancy outcomes for women dispensed an SSRI in pregnancy. METHODS: Using data linkage of population-based health datasets from Western Australia and a national pharmaceutical claims dataset, our study included 123,405 pregnancies from 2002 to 2005. There were 3764 children born to 3703 women who were dispensed an SSRI during their pregnancy. RESULTS: A total of 42.3% of the women were dispensed an SSRI in each trimester, and 97.6% of the women used the same SSRI throughout the first trimester without switching. The women who were dispensed an SSRI were more likely to give birth prematurely (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.2-1.7), to have smoked during the pregnancy (OR, 1.9; 95% CI, 1.8-2.1), and parity>1 (OR, 1.7; 95% CI, 1.5-1.8). The singletons were found to have a lower birth weight than expected when other factors were taken into account (OR, 1.2; 95% CI, 1.1-1.3). There was an increased risk of major cardiovascular defects (OR, 1.6; 95% CI, 1.1-2.3). The children of women dispensed citalopram during the first trimester had an increased risk of vesicoureteric reflux (OR, 3.1; 95% CI, 1.3-7.6). Children born to women dispensed sertraline had a higher mean birth weight than those born to women dispensed citalopram, paroxetine, or fluoxetine. This pattern was also seen in birth length. CONCLUSIONS: Most women were dispensed the same SSRI throughout their pregnancy. We have confirmed previous findings with an increased risk of cardiovascular defects and preterm birth. New findings requiring confirmation include an increased risk of vesicoureteric reflux with the use of citalopram.

Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens.

PURPOSE: Data linkage of population administrative data is being investigated as a tool for pharmacovigilance in pregnancy in Australia. Records of prescriptions of known or suspected teratogens dispensed to pregnant women have been linked to a birth defects registry to determine if defects associated with medicine exposure can be detected. METHODS: The Pharmaceutical Benefits Scheme is a national claims database that has been linked with population-based data to extract linkages for women with a pregnancy event in Western Australia from 2002 to 2005 (n = 106 074). Records of births to the women who were dispensed medicines in categories D or X of the Australian ADEC pregnancy risk category were linked to the Birth Defects Registry of Western Australia. Population rates of registered birth defects per 1000 births were calculated for each medicine. RESULTS: There were 47 medicines dispensed at least once during pregnancy with 23 associated with a registered birth defect to a woman dispensed the medicine. When the birth defect rate for each medicine was compared with the rate for all other women not dispensed that medicine, most medicines showed an increased risk. Medicines with the higher risks were medroxyprogesterone acetate (OR: 1.8; 95%CI: 1.4-2.3), follitropin alfa (OR: 2.5; 95%CI: 1.2-5.0), carbamazepine (OR: 3.1; 95%CI: 1.7-5.6) and enalapril maleate (OR: 8.1; 95%CI: 1.6-41.7). CONCLUSION: Many known associations between medicines and birth defects were identified, suggesting that linked administrative data could be an important means of pharmacovigilance in pregnancy in Australia.

A retrospective population-based study of childhood hospital admissions with record linkage to a birth defects registry.

BACKGROUND: Using population-based linked records of births, deaths, birth defects and hospital admissions for children born 1980-1999 enables profiles of hospital morbidity to be created for each child. METHODS: This is an analysis of a state-based registry of birth defects linked to population-based hospital admission data. Transfers and readmissions within one day could be taken into account and treated as one episode of care for the purposes of analyses (N = 485,446 children; 742,845 non-birth admissions). RESULTS: Children born in Western Australia from 1980-1999 with a major birth defect comprised 4.6% of live births but 12.0% of non-birth hospital admissions from 1980-2000. On average, the children with a major birth defect remained in hospital longer than the children in the comparison group for the same diagnosis. The mean and median lengths of stay (LOS) for admissions before the age of 5 years have decreased for all children since 1980. However, the mean number of admissions per child admitted has remained constant at around 3.8 admissions for children with a major birth defect and 2.2 admissions for all other children. CONCLUSION: To gain a true picture of the burden of hospital-based morbidity in childhood, admission records need to be linked for each child. We have been able to do this at a population level using birth defect cases ascertained by a birth defects registry. Our results showed a greater mean LOS and mean number of admissions per child admitted than previous studies. The results suggest there may be an opportunity for the children with a major birth defect to be monitored and seen earlier in the primary care setting for common childhood illnesses to avoid hospitalisation or reduce the LOS.

Twins born following assisted reproductive technology: perinatal outcome and admission to hospital.

BACKGROUND: Compared with spontaneously conceived (SC) singletons, adverse perinatal outcome, neonatal intensive care unit (NICU) admission and hospital admission in infancy are more common in those born following Assisted Reproductive Technology (ART). Similar comparisons for twins have shown conflicting results. METHODS: We investigated perinatal outcome and hospital admission during the first 3 years of life for all twin children born in Western Australia between 1994 and 2000 [700 ART, 4097 SC]. RESULTS: ART twins had a greater risk of adverse perinatal outcome including preterm birth, low birthweight and death compared with SC twins of unlike-sex. In their first year of life, ART twins had a longer birth admission; were 60% more likely to be admitted to a NICU; and had a higher risk of hospital admission. The increased risk of hospital admission continued in the second and third year but was not statistically significant in the third year. CONCLUSIONS: Couples undertaking ART should be aware that in addition to the known increased perinatal risks associated with a twin birth, ART twins are more likely than SC twins to be admitted to a NICU and hospitalized in the first 3 years of life.

Pharmacovigilance in pregnancy using population-based linked datasets.

PURPOSE: National dispensing data for subsidized prescription medicines have recently been approved for linkage to the population-based health datasets in Western Australia (WA), creating the capacity to study how these medicines are used and their impact on pregnancy outcomes. METHODS: Pregnancy events were identified in the Hospital Morbidity Data System from 2002 to 2005 (N = 164,278 admissions; N = 98,265 women) and linked to the midwives' notification system (MNS), the registry of births and deaths, the Western Australian birth defects registry and the pharmaceutical benefit scheme. Dispensing records were extracted for each pregnancy event (N = 1,276,084 dispenses). RESULTS: There were 106,074 births, 1527 ectopic pregnancies and 25,180 terminations of pregnancy. Dispensed medicines were linked to 28.0% of the pregnancy events. Multiple birth pregnancies were 50% more likely to be dispensed a medicine in the first trimester. As parity increased, so did the likelihood of a medicine being dispensed in pregnancy. Women who were dispensed a medicine were twice as likely to smoke during pregnancy and were 14% more likely to have a registered birth defect. During the first trimester, medicines from category D or X of the risk of drug use in pregnancy were dispensed to 2.1% of all pregnancy events. The WHO ATC 'Psychoanaleptics' category was dispensed to 3.8% of all pregnancy events. CONCLUSION: Linkage of dispensing data to pregnancy events is feasible and this approach to post-marketing surveillance will add to the resources available in Australia to investigate pregnancy outcomes in relation to the safe use of prescribed medicines in pregnancy.

Admission to hospital of singleton children born following assisted reproductive technology (ART).

BACKGROUND: Adverse perinatal outcomes are more common in singletons born following assisted reproductive technology (ART) and this would predict an increase in hospitalization during infancy and early childhood. METHODS: We investigated hospital admissions during the first 3 years of life for all singleton children born in Western Australia between 1994 and 2000 [1328 ART, 162 350 spontaneously conceived (SC)]. RESULTS: ART infants had a significantly longer birth admission and were four times more likely to be admitted to neonatal intensive care units (NICU) than SC infants. ART children had a 60% greater risk of one or more admissions in their first year and an equal risk of admission in their second and third years. Their length of stay in hospital was longer in each age period. Maternal, infant and socio-economic confounders accounted for most of the increased admission risk in the first year. However, after adjustment, a 20% increase in the risk of admission to NICU (P < 0.05) and admission to hospital during the first year (P < 0.05) remained. CONCLUSIONS: Couples undertaking ART should be aware that ART infants are more likely to be admitted to a NICU, to be hospitalized in the first year of life and to stay in hospital longer than other children.

Alcohol consumption during pregnancy in nonindigenous west Australian women.

BACKGROUND: High alcohol intake in pregnancy has been linked to abnormal fetal development. There are limited published data in Australia on standard drinks of alcohol consumed on a typical occasion during the periconceptional period or pregnancy. METHODS: During 1995 to 1997, a 10% random sample of all nonindigenous women giving birth in Western Australia was surveyed 12 weeks after delivery (N=4,839). Women were asked questions about alcohol consumption in each of the 4 time periods: the 3 months before pregnancy and each trimester of pregnancy. Questions were framed to measure volume, frequency, and type of alcoholic beverage. RESULTS: 46.7% of the women had not planned their pregnancy. Most women (79.8%) reported drinking alcohol in the 3 months before pregnancy, with 58.7% drinking alcohol in at least 1 trimester of pregnancy. The proportion of women consuming 1 to 2 drinks on a typical occasion did not change much during pregnancy, but the number of occasions declined. Although the proportion of women consuming more than 2 standard drinks on a typical occasion declined after the first trimester, 19.0% of women consumed this amount in at least 1 trimester of pregnancy and 4.3% of women consumed 5 or more standard drinks on a typical occasion in at least 1 trimester of pregnancy. In the first trimester of pregnancy, 14.8% of women drank outside the current Australian guideline for alcohol consumption in pregnancy, decreasing to 10% in the second and third trimesters. CONCLUSIONS: Women generally reduced their average alcohol consumption and the number of standard drinks on a typical occasion as their pregnancy progressed, although 10 to 14% were drinking outside current guidelines for pregnancy. It is important that all women of child-bearing age are aware, well before they consider pregnancy, of the risks of drinking alcohol during pregnancy so they can make informed decisions about their alcohol consumption in pregnancy.

Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation.

INTRODUCTION: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing. METHODS: Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated. RESULTS: Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations. CONCLUSIONS: XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.

Health service use in Rett syndrome.

Rett syndrome is a severe neurodevelopmental disorder affecting girls, caused by mutations in the MECP2 gene. There are no population-based data on the extent and determinants of health service use in this disorder. The population-based registry, the Australian Rett Syndrome database, was the source of phenotype data. This also contains data from mutation screening and X-inactivation studies. Data on retrospective (n = 152) and prospective (n = 162) health service use were collected in 2000 from a questionnaire and a calendar study, respectively. Health service use was highest in younger cases (P = .001) and lowest in cases with milder phenotypes (P < .001). Random X-inactivation was associated with service use (P = .02). Maternal education, phenotype, and individual mutations were determinants of health service use. The use of a retrospective and prospective data set enabled accurate assessment of service use in Rett syndrome. Both genetic and sociodemographic determinants of health service use were identified, with important implications for the optimal and equitable management of children with Rett syndrome.

Hand preference, extent of laterality, and functional hand use in Rett syndrome.

Residual hand use in functional tasks, extent of laterality, and right or left preference were studied in 145 2- to 24-year-old, postregression Australian subjects with Rett syndrome via parent questionnaire. Hand use was markedly restricted, more for complex than simple and for external (touching food and objects) than internal tasks (scratching, rubbing eyes), suggesting a deficit in cerebral control of external, goal-oriented hand use, which is perhaps genetically determined because there is significantly greater restriction of external tasks in subjects with demonstrated MECP2 mutations. Overall, 33.6% of patients were reported with a left-hand preference, 40.7% with a right-hand preference, and 25.7% with an equal hand preference. Extent of laterality was greater for external than internal and for complex than simple external tasks. Older subjects showed less functional hand use and possibly more overall laterality. However, their hand preference was similar to younger subjects. The anomalous pattern of hand preference in Rett syndrome may be linked to the primary apraxic deficit in this disorder rather than to late manifestation of laterality.