Association between cumulative maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder: A cohort study.

BACKGROUND: Preclinical studies suggest synergistic effects of maternal inflammatory exposures on offspring neurodevelopment, but human studies have been limited. OBJECTIVES: To examine the cumulative association and potential interactions between seven maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a population-based cohort study of children born from July 2001 to December 2011 in New South Wales, Australia, and followed up until December 2014. Seven maternal exposures were identified from birth data and hospital admissions during pregnancy: autoimmune disease, asthma, hospitalization for infection, mood or anxiety disorder, smoking, hypertension, and diabetes. Child ADHD was identified from stimulant prescription records. Multivariable Cox regression assessed the association between individual and cumulative exposures and ADHD and potential interaction between exposures, controlling for potential confounders. RESULTS: The cohort included 908,770 children, one-third (281,724) with one or more maternal exposures. ADHD was identified in 16,297 children (incidence 3.5 per 1000 person-years) with median age of 7 (interquartile range 2) years at first treatment. Each exposure was independently associated with ADHD, and risk increased with additional exposures: one exposure (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.54, 1.65), two exposures (HR 2.25, 95% CI 2.13, 2.37), and three or more exposures (HR 3.28, 95% CI 2.95, 3.64). Positive interaction was found between smoking and infection. The largest effect size was found for cumulative exposure of asthma, infection, mood or anxiety disorder, and smoking (HR 6.12, 95% CI 3.47, 10.70). CONCLUSIONS: This study identifies cumulative effects of multiple maternal exposures related to inflammation on ADHD, most potentially preventable or modifiable. Future studies should incorporate biomarkers of maternal inflammation and consider gene-environment interactions.

Using novel data linkage of congenital heart disease biobank data with administrative health data to identify cardiovascular outcomes to inform genomic analysis.

Introduction: Contemporary care of congenital heart disease (CHD) is largely standardised, however there is heterogeneity in post-surgical outcomes that may be explained by genetic variation. Data linkage between a CHD biobank and routinely collected administrative datasets is a novel method to identify outcomes to explore the impact of genetic variation. Objective: Use data linkage to identify and validate patient outcomes following surgical treatment for CHD. Methods: Data linkage between clinical and biobank data of children born from 2001-2014 that had a procedure for CHD in New South Wales, Australia, with hospital discharge data, education and death data. The children were grouped according to CHD lesion type and age at first cardiac surgery. Children in each 'lesion/age at surgery group' were classified into 'favourable' and 'unfavourable' cardiovascular outcome groups based on variables identified in linked administrative data including; total time in intensive care, total length of stay in hospital, and mechanical ventilation time up to 5 years following the date of the first cardiac surgery. A blind medical record audit of 200 randomly chosen children from 'favourable' and 'unfavourable' outcome groups was performed to validate the outcome groups. Results: Of the 1872 children in the dataset that linked to hospital or death data, 483 were identified with a 'favourable' cardiovascular outcome and 484 were identified as having a 'unfavourable' cardiovascular outcome. The medical record audit found concordant outcome groups for 182/192 records (95%) compared to the outcome groups categorized using the linked data. Conclusions: The linkage of a curated biobank dataset with routinely collected administrative data is a reliable method to identify outcomes to facilitate a large-scale study to examine genetic variance. These genetic hallmarks could be used to identify patients who are at risk of unfavourable cardiovascular outcomes, to inform strategies for prevention and changes in clinical care.

Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review.

Inflammation is increasingly recognized as a cause or consequence of common problems of humanity including obesity, stress, depression, pollution and disease states such as autoimmunity, asthma, and infection. Maternal immune activation (MIA), triggered by both acute and systemic chronic inflammation, is hypothesized to be one of the mechanisms implicated in the pathogenesis of neurodevelopmental disorders (NDD). Although there is substantial preclinical evidence to support the MIA hypothesis, the human evidence is disparate. We performed a systematic review on human studies examining associations between maternal inflammatory states and offspring NDDs (autism spectrum disorder- ASD, attention deficit hyperactivity disorder-ADHD, Tourette syndrome-TS). 32 meta-analyses and 26 additional individual studies were identified. Maternal states associated with ASD include obesity, gestational diabetes mellitus, pre-eclampsia, pollution, stress, depression, autoimmune diseases, and infection. Maternal states associated with ADHD include obesity, pre-eclampsia, smoking, low socioeconomic status (SES), stress, autoimmune disease, and asthma. Maternal states associated with TS include low SES, depression, and autoimmune diseases. Diverse maternal inflammatory states in pregnancy are associated with common offspring NDDs. Given the increased prevalence of NDDs, there is urgent need to explore relative and cumulative maternal risk factors and disease mechanisms. Defining preventable risk factors in high-risk pregnancies could mitigate the expression and severity of NDDs.

School-Age Developmental and Educational Outcomes Following Cardiac Procedures in the First Year of Life: A Population-Based Record Linkage Study.

The purpose of the study was to evaluate school-age developmental and educational outcomes for children with and without a cardiac procedure in the first year of life to improve understanding of longer-term neurodevelopmental outcomes in children who have had a cardiac procedure for congenital heart disease, the most common serious congenital anomaly. A population-based cohort study using record linkage of state-wide data was undertaken, evaluating children born in New South Wales, Australia, 2001-2007. Those with and without a cardiac procedure in the first year of life with a linked developmental (Australian version Early Development Instrument testing result, age 4-6 years) and/or educational outcome (Australian National Assessment Program result, age 7-9 years) were included. Perinatal, perioperative and sociodemographic factors were examined using multivariable logistic regression models. Of 468,329 eligible children, 768 had a cardiac procedure in the first year of life and 582 were included. For those with a cardiac procedure and developmental outcome (n = 260), 13.1% were classified as having 'special needs' compared to 4.4% without a cardiac procedure. Of those with an educational outcome, after adjusting for perinatal, perioperative and demographic variables, children with a cardiac procedure (n = 396) were twice as likely to score below National Minimum Standard in school literacy and numeracy tests compared to their peers. Significant predictors included low birthweight, parent not completing school and having > 4 re-hospitalisations in their first six years. The developmental and educational trajectory of children who have had a cardiac procedure in their first year remains altered into primary school years. While perioperative factors did not impact outcomes, ongoing health and sociodemographic factors were important in identifying those children at greatest risk.

The impact of general anesthesia on child development and school performance: a population-based study.

BACKGROUND: There has been considerable interest in the possible adverse neurocognitive effects of exposure to general anesthesia and surgery in early childhood. AIMS: The aim of this data linkage study was to investigate developmental and school performance outcomes of children undergoing procedures requiring general anesthesia in early childhood. METHODS: We included children born in New South Wales, Australia of 37+ weeks' gestation without major congenital anomalies or neurodevelopmental disability with either a school entry developmental assessment in 2009, 2012, or Grade-3 school test results in 2008-2014. We compared children exposed to general anesthesia aged <48 months to those without any hospitalization. Children with only 1 hospitalization with general anesthesia and no other hospitalization were assessed separately. Outcomes included being classified developmentally high risk at school entry and scoring below national minimum standard in school numeracy and reading tests. RESULTS: Of 211 978 children included, 82 156 had developmental assessment and 153 025 had school test results, with 12 848 (15.7%) and 25 032 (16.4%) exposed to general anesthesia, respectively. Children exposed to general anesthesia had 17%, 34%, and 23% increased odds of being developmentally high risk (adjusted odds ratio [aOR]: 1.17; 95% CI: 1.07-1.29); or scoring below the national minimum standard in numeracy (aOR: 1.34; 95% CI: 1.21-1.48) and reading (aOR: 1.23; 95% CI: 1.12-1.36), respectively. Although the risk for being developmentally high risk and poor reading attenuated for children with only 1 hospitalization and exposure to general anesthesia, the association with poor numeracy results remained. CONCLUSION: Children exposed to general anesthesia before 4 years have poorer development at school entry and school performance. While the association among children with 1 hospitalization with 1 general anesthesia and no other hospitalization was attenuated, poor numeracy outcome remained. Further investigation of the specific effects of general anesthesia and the impact of the underlying health conditions that prompt the need for surgery or diagnostic procedures is required, particularly among children exposed to long duration of general anesthesia or with repeated hospitalizations.

Mortality, rehospitalizations and costs in children undergoing a cardiac procedure in their first year of life in New South Wales, Australia.

BACKGROUND: Cardiac procedures are part of management for many children with congenital heart disease (CHD). Using population health data, this study explores health outcomes of children undergoing a cardiac procedure in the first year of life to better understand the impact of CHD on children, families and health services. METHODS AND RESULTS: A population-based record-linkage cohort study was undertaken. Rate of cardiac procedures in the first year of life over the study period 2001-2012 in New South Wales, Australia, was steady at 2.5 children per 1000 live births, accounting for 2722 children. Excluding those with isolated closure of patent ductus arteriosus (n=416), 50% required readmission in the first year of life. Over 1/5th had an additional non-cardiac congenital anomaly. Average total cost per infant for initial procedure admission was $67,054 AUD ($63,124-$70,984) with a median length of stay (LOS) 13days (IQR 8-23). Average cost per readmission in the first year of life was $11,342 (95% CI 10,361-$12,323) with median LOS 2days (IQR 1-5). Mortality rate in the 30days following initial procedure was 3.1% (72/2306). Mortality rate by age 1year was 7.1%, and 13.8% for those who had neonatal surgery. CONCLUSION: Risk of mortality in operatively-managed CHD extends beyond the immediate perioperative period. Children undergoing a cardiac procedure in their first year are often readmitted to hospital for both further planned procedures and unplanned reasons such as infection. These readmissions capture the significant impact of illness and pose substantial financial cost to the health system.

Early Childhood Development of Boys with Genital Anomalies.

BACKGROUND: Male genital anomalies often require surgery in early life to address functional and cosmetic consequences. However, there has been little assessment of developmental outcomes of affected boys. METHODS: We conducted a population-based cohort study of all boys born in New South Wales, Australia, and undergoing school-entry developmental assessment in 2009 or 2012. Health and developmental information was obtained by means of record-linkage of birth, hospital and Australian Early Development Census data. Boys with hypospadias or undescended testis (UDT) were compared with those without. Developmental outcomes were assessed in five domains (physical health, emotional maturity, communication, cognitive skills, and social competence), and boys were categorized as vulnerable (<10th centile of national scores), developmentally high risk (DHR; vulnerable in 2+ domains), and special needs. RESULTS: We included 420 boys with hypospadias, 873 with UDT, and 77,176 unaffected boys. There was no difference in the proportion of boys developmentally vulnerable in any domain or DHR between boys with hypospadias (DHR: n = 49; 13.1%; p = 0.9), UDT (n = 116; 15.2%; p = 0.06), and unaffected boys (n = 9278; 12.9%). Compared with unaffected boys (n = 4826; 6.3%), boys with hypospadias (n = 43; 10.2%; p < 0.001) or UDT (n = 105; 12.0%; p < 0.001) were more likely to have special needs. Stratified analyses revealed that only boys with UDT and coexisting anomalies had increased risk of being DHR (odds ratio: 2.65; 95% confidence interval, 1.61-4.36) or special needs (odds ratio: 2.91; 95% confidence interval, 2.00-4.22). CONCLUSION: We found no increased risk of poor development among boys with hypospadias or UDT. However, boys with UDT and coexisting anomalies were more likely to have poorer development and special needs. Birth Defects Research 109:535-542, 2017. © 2017 Wiley Periodicals, Inc.

Trends in New South Wales infant hospital readmission rates in the first year of life: a population-based study.

OBJECTIVE: To examine the trends in hospital readmissions in the first year of life and identify whether changes in maternal and infant risk factors explain any changes. DESIGN: Population-based study using de-identified linked health data. PARTICIPANTS: All 788 798 live-born infants delivered in New South Wales from 1 January 2001 to 31 December 2009 with a linked birth and hospital record. MAIN OUTCOME MEASURES: The number of infants readmitted to hospital at least once after discharge home from the birth admission to 1 year of age, per 100 live births each year, and changes in maternal and infant risk factors assessed by logistic regression. RESULTS: The number of infants readmitted to hospital up to age 1 year decreased by 10.5% (average annual reduction, 1.8%; 95% CI, - 1.7% to - 0.01%, P = 0.001), from 18.4 per 100 births in 2001 to 16.5 in 2009. Fifty-five per cent of this decrease could be explained by changes in factors that are associated with likelihood of hospitalisation; length of stay during the birth admission, maternal age and maternal smoking. The rate of readmissions for jaundice and feeding difficulties increased significantly over the study period, while readmissions for infections decreased. CONCLUSIONS: There has been a decrease in the rate of infants readmitted to hospital in the first year of life, which can be partly explained by increasing maternal age, decreasing maternal smoking and a shift to shorter length of hospital stay at birth. Improved maternal and neonatal care in hospital and increased postnatal support at home may have contributed to reduced risk of readmission.

Record linkage to obtain birth outcomes for the evaluation of screening biomarkers in pregnancy: a feasibility study.

BACKGROUND: Linking population health data to pathology data is a new approach for the evaluation of predictive tests that is potentially more efficient, feasible and efficacious than current methods. Studies evaluating the use of first trimester maternal serum levels as predictors of complications in pregnancy have mostly relied on resource intensive methods such as prospective data collection or retrospective chart review. The aim of this pilot study is to demonstrate that record-linkage between a pathology database and routinely collected population health data sets provides follow-up on patient outcomes that is as effective as more traditional and resource-intensive methods. As a specific example, we evaluate maternal serum levels of PAPP-A and free beta-hCG as predictors of adverse pregnancy outcomes, and compare our results with those of prospective studies. METHODS: Maternal serum levels of PAPP-A and free beta-hCG for 1882 women randomly selected from a pathology database in New South Wales (NSW) were linked to routinely collected birth and hospital databases. Crude relative risks were calculated to investigate the association between low levels (multiples of the median < or = 5th percentile) of PAPP-A or free beta-hCG and the outcomes of preterm delivery (<37 weeks), small for gestational age (<10th percentile), fetal loss and stillbirth. RESULTS: Using only full name, sex and date of birth for record linkage, pregnancy outcomes were available for 1681 (89.3%) of women included in the study. Low levels of PAPP-A had a stronger association with adverse pregnancy outcomes than a low level of free beta-hCG which is consistent with results in published studies. The relative risk of having a preterm birth with a low maternal serum PAPP-A level was 3.44 (95% CI 1.96-6.10) and a low free beta-hCG level was 1.31 (95% CI 0.55-6.16). CONCLUSION: This study provides data to support the use of record linkage for outcome ascertainment in studies evaluating predictive tests. Linkage proportions are likely to increase if more personal identifiers are available. This method of follow-up is a cost-efficient technique and can now be applied to a larger cohort of women.

Are babies getting bigger? An analysis of birthweight trends in New South Wales, 1990-2005.

OBJECTIVE: To determine whether the proportion of babies born large for gestational age (LGA) in New South Wales has increased, and to identify possible reasons for any increase. DESIGN AND SETTING: Population-based study using data obtained from the NSW Midwives Data Collection, a legislated surveillance system of all births in NSW. PARTICIPANTS: All 1 273 924 live-born singletons delivered at term (> or = 37 complete weeks' gestation) in NSW from 1990 to 2005. MAIN OUTCOME MEASURES: LGA, defined as > 90th centile for sex and gestational age using 1991-1994 Australian centile charts; maternal factors associated with LGA were assessed using logistic regression. RESULTS: The proportion of babies born LGA increased from 9.2% to 10.8% (18% increase) for male infants and from 9.1% to 11.0% (21% increase) for female infants. The mean birthweight increased by 23 g for boys and 25 g for girls over the study period. Increasing maternal age, higher rates of gestational diabetes and a decline in smoking contributed significantly to these increases, but did not fully explain them. CONCLUSIONS: There is an increasing trend in the proportion of babies born LGA, which is only partly attributable to decreasing maternal smoking, increasing maternal age and increasing gestational diabetes.