Estimating the Prevalence of Autism Spectrum Disorder in New South Wales, Australia: A Data Linkage Study of Three Routinely Collected Datasets.

Routinely collected data help estimate the prevalence of autism spectrum disorder (ASD) in jurisdictions without active autism surveillance. We created a population-based cohort of 1,211,834 children born in 2002-2015 in New South Wales, Australia using data linkage. Children with ASD were identified in three datasets - disability services, hospital admissions, and ambulatory mental health data. The prevalence of ASD in the cohort was 1.3% by age 12 and prevalence at age 6 increased an average of 4.1% per year (95% Confidence Interval, 3.3%, 4.8%). Most children with ASD were identified in disability services data (87%), although data linkage identified 1,711 additional cases that were more likely female, older at first contact, and living in major cities and less disadvantaged areas.

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.

A comparison of cohorts of children with cerebral palsy from a population register and hospital admission data: A data linkage study.

BACKGROUND: Administrative health data, such as hospital admission data, are often used in research to identify children/young people with cerebral palsy (CP). OBJECTIVES: To compare sociodemographic, clinical details and mortality of children/young people identified as having CP in either a CP population registry or hospital admission data. METHODS: We identified two cohorts of children/young people (birth years 2001-2010, age at study end or death 2 months to 19 years 6 months) with a diagnosis of CP from either (i) the New South Wales (NSW)/Australian Capital Territory (ACT) CP Register or (ii) NSW hospital admission data (2001-2020). Using record linkage, these data sources were linked to each other and NSW Death, Perinatal, and Disability datasets. We determined the sensitivity and positive predictive value (PPV) of CP diagnosis in hospital admission data compared with the NSW/ACT CP Register (gold standard). We then compared the sociodemographic and clinical characteristics and mortality of the two cohorts available through record linkage using standardised mean difference (SMD). RESULTS: There were 1598 children/young people with CP in the NSW/ACT CP Register and 732-2439 children/young people with CP in hospital admission data, depending on the case definition used. The sensitivity of hospital admission data for diagnosis of CP ranged from 0.40-0.74 and PPV 0.47-0.73. Compared with children/young people with CP identified in the NSW/ACT CP Register, a greater proportion of those identified in hospital admission data (one or more admissions with G80 case definition) were older, lived in major cities, had comorbidities including epilepsy, gastrostomy use, intellectual disability and autism, and died during the study period (SMD > 0.1). CONCLUSIONS: Sociodemographic and clinical characteristics differ between cohorts of children/young people with CP identified using a CP register or hospital admission data. Those identified in hospital admission data have higher rates of comorbidities and death, suggesting some may have progressive conditions and not CP. These differences should be considered when planning and interpreting research using various data sources.

Outcomes of lowered newborn screening thresholds for congenital hypothyroidism.

BACKGROUND: Newborn screening (NBS) has largely eliminated the physical and neurodevelopmental effects of untreated congenital hypothyroidism (CH). Many countries, including Australia, have progressively lowered NBS bloodspot thyroid-stimulating hormone (b-TSH) thresholds. The impact of these changes is still unclear. OBJECTIVES: To evaluate the performance of CH NBS following the reduction of b-TSH thresholds in New South Wales (NSW) and the Australian Capital Territory (ACT), Australia, from 15 to 8 mIU/L, and to determine the clinical outcomes of cases detected by these thresholds. METHODS: NBS data of 346 849 infants born in NSW/ACT, Australia from 1 November, 2016-1 March, 2020 inclusive were analysed. A clinical audit was conducted on infants with a preliminary diagnosis of CH born between 1 January, 2016-1 December, 2020 inclusive. RESULTS: The lowered b-TSH threshold (≥8 mIU/L, ~99.5th centile) detected 1668 infants (0.48%), representing an eight-fold increase in recall rate, of whom 212 of 1668 (12.7%) commenced thyroxine treatment. Of these 212 infants, 62 (29.2%) (including eight cases with a preliminary diagnosis of thyroid dysgenesis) had an initial b-TSH 8-14.9 mIU/L. The positive predictive value for a preliminary diagnosis of CH decreased from 74.3% to 12.8% with the lowered threshold. Proportionally, more pre-term infants received a preliminary CH diagnosis on screening with the lower threshold (16.1% of 62) than with the higher threshold (8.0% of 150). CONCLUSION: Clinically relevant CH was detected using the lowered threshold, albeit at the cost of an eight-fold increase in recall rate. Further clinical and economic studies are required to determine whether benefits of lowered screening thresholds outweigh potential harms from false-positive results on infants, their families and NBS programs.

Child characteristics and health conditions associated with paediatric hospitalisations and length of stay: a population-based study.

Background: Paediatric hospital length of stay (LoS) is often used as a benchmark for resource use of hospitalisations. Previous studies have mostly focused on LoS of admissions for specific conditions or medical specialties. We aimed to conduct an evaluation of LoS of all paediatric hospitalisations exploring the frequency and characteristics; and associated childhood conditions. Methods: This population-based cross-sectional study included all hospital admissions in children aged <16 years between January 2017 and December 2019 in New South Wales, Australia. LoS was categorised into: day or overnight stay, 2-7, 8-21 and ≥ 22 days. Socio-demographic and health service characteristics of each individual admission by LoS and age groups were evaluated. Findings: A total of 324,083 children had 518,768 admissions comprising 1,064,032 bed days. Most admissions wereday/overnight stays (71.9%) or 2-7 days (25.3%). While LoS >7 days represented 2.8% of total admissions, they accounted for 27% of total bed days. Children aged 1-4 years had the highest proportion of admissions (35%), with a majority lasting ≤7 days, whereas 45.6% of admissions ≥22 days were for children aged ≥12 years. Respiratory conditions, diseases of the digestive system and traumatic injuries were the most common reasons for hospitalization. LoS >7 days were more common in children from most disadvantaged backgrounds, residing further from hospital and those aged ≥12 years with mental health conditions. Interpretation: The majority of paediatric hospitalizations are for short stay and require programs that target acute conditions that can be managed in primary care. Interventions such as care coordination, tailored models of care and enhanced outpatient/community treatment programs for high-risk groups will help reduce extended LoS and improving child health and well-being. Funding: Australian National Health and Medical Research Council.

Examination of validity of identifying congenital heart disease from hospital discharge data without a gold standard: Using a data linkage approach.

BACKGROUND: Administrative health data has been used extensively to examine congenital heart disease (CHD). However, the accuracy and completeness of these data must be assessed. OBJECTIVES: To use data linkage of multiple administrative data sources to examine the validity of identifying CHD cases recorded in hospital discharge data. METHODS: We identified all liveborn infants born 2013-2017 in New South Wales, Australia with a CHD diagnosis up to age one, recorded in hospital discharge data. Using record linkage to multiple data sources, the diagnosis of CHD was compared with five reference standards: (i) multiple hospital admissions containing CHD diagnosis; (ii) receiving a cardiac procedure; (iii) CHD diagnosis in the Register of Congenital Conditions; (iv) cardiac-related outpatient health service recorded; and/or (v) cardiac-related cause of death. Positive predictive values (PPV) comparing CHD diagnosis with the reference standards were estimated by CHD severity and for specific phenotypes. RESULTS: Of 485,239 liveborn infants, there were 4043 infants with a CHD diagnosis identified in hospital discharge data (8.3 per 1000 live births). The PPV for any CHD identified in any of the five methods was 62.8% (95% confidence interval [CI] 60.9, 64.8), with PPV higher for severe CHD at 94.1% (95% CI 88.2, 100). Infant characteristics associated with higher PPVs included lower birthweight, presence of a syndrome or non-cardiac congenital anomaly, born to mothers aged <20 years and residing in disadvantaged areas. CONCLUSION: Using data linkage of multiple datasets is a novel and cost-effective method to examine the validity of CHD diagnoses recorded in one dataset. These results can be incorporated into bias analyses in future studies of CHD.

Clinical survey of current practice regarding treatment of children with borderline thyroid abnormalities.

AIM: Recently, there has been debate about reducing newborn screening (NBS) thyroid-stimulating hormone (TSH) cut-offs to identify children with mild, but potentially clinically significant, thyroid deficiency. Once identified by NBS, these children will be referred to paediatric endocrinologists for further testing and possible treatment; however, variation in current clinical practice is not known. The aim of this study is to survey Paediatric Endocrinologists in Australia and New Zealand to gain insight into clinical practice for the treatment of mild thyroid deficiency. METHODS: A piloted questionnaire was sent to members of the Australasian Paediatric Endocrinologist Group. The survey asked the Australasian Paediatric Endocrinologist Group members about the investigations performed, treatment and follow-up for infants with different confirmatory serum TSH levels. RESULTS: There were 42 completed surveys, a response rate of 34%. When presented with four case studies, 7% of clinicians would treat a child with confirmatory serum TSH of 8.7 mU/L with thyroxine, 69% would treat a child with confirmatory serum TSH 21.4 mU/L, 76% would treat a child with confirmatory serum TSH 24.3 mU/L and 95% would treat a child with confirmatory serum TSH 44.7 mU/L. CONCLUSION: This contemporary survey of clinicians regarding the treatment of mild thyroid deficiency in children has shown that clinical practice varies extensively. International and national guidelines on the treatment of congenital hypothyroidism should be updated to incorporate new evidence and ensure consistency across clinical practice.

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.

Association of maternal autoimmune disease and early childhood infections with offspring autism spectrum disorder: A population-based cohort study.

The aim of this study was to examine potential synergistic effects between maternal autoimmune disease and early childhood infections and their association with autism spectrum disorder (ASD) in offspring. Both exposures have been associated with increased risk of ASD in previous studies, but potential synergistic effects remain underexplored. We conducted a population-based cohort study of singleton children born at term gestation (37-41 weeks) in New South Wales, Australia from January 2002 to December 2008. Maternal autoimmune diagnoses and childhood infections before age 2 years were identified from linked maternal and child hospital admissions, and ASD diagnoses by age 9 years were identified from linked disability services data. Multivariable logistic regression assessed the association between each exposure and ASD and additive interaction between exposures, controlling for potential confounders. A total of 18,451 children exposed to maternal autoimmune disease were propensity score matched (1:2) to 36,902 unexposed children. Any maternal autoimmune disease (adjusted odds ratio (aOR) 1.25, 95% confidence interval (CI) 1.07-1.47) and any childhood infection before age 2 years (aOR 1.38, 95% CI 1.15-1.67) were each associated with ASD. However, there was no evidence of additive interaction between the two exposures (relative excess risk due to interaction [RERI] 0.128, 95% CI -0.418-0.675) resulting in increased odds of ASD in offspring. Future studies could examine potential interactions between other sources of maternal immune activation and childhood infection and impact on ASD and other neurodevelopmental disorders.

DIFFERENTIAL IMPACT OF PERIODONTAL TREATMENT STRATEGIES DURING PREGNANCY ON PERINATAL OUTCOMES: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVES: This study aimed to evaluate the impact of different periodontal treatment strategies during pregnancy on perinatal outcomes. STUDY SELECTION: This systematic review and meta-analysis of clinical trials was conducted according to PRISMA guidelines to assess the effect of mouthwash in addition to scaling and root planning (SRPM) on pregnancy outcomes, including preterm birth, low birth weight, gestational age, and birth weight. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (CI) were calculated using the random effect model. RESULTS: Twenty trials involving 5938 participants, including thirteen trials comparing scaling and root planning (SRP) and seven trials comparing SRPM with control groups. SRPM was associated with reduced risk of preterm birth (RR = 0.37; 95%CI = 0.16-0.84; P = .017; I2=93.26%; P < .001; number needed to treat (NNT): 3), low birth weight (RR = 0.54; 95%CI = 0.40-0.74; P < .0001; I2 = 0%; P = .46; NNT: 13), increased gestational age (MD = 0.78; 95%CI: 0.19-1.37; P = .009; I2 = 87.15%; P < .001), and birth weight (MD = 121.77; 95%CI = 3.19-240.34; P = .044; I2 = 80.68%; P < .001). There were no statistically significant differences in the analysis of SRP group, except for the increased birth weight (MD = 93.85; 95% CI = 3.27-184.42; P = .042; I2 = 84.11%; P < .001). CONCLUSION: Using mouthwash in addition to scaling and root planning (SRPM) for the treatment of periodontal disease during pregnancy significantly improves perinatal outcomes.

Prevalence of autoimmune disease among pregnant women and women of reproductive age in New South Wales, Australia: a population-based study.

BACKGROUND: Autoimmune diseases disproportionately affect women and have been linked to increased risk of maternal and perinatal mortality and morbidity. Our aim was to determine the prevalence of autoimmune disease among pregnant women and women of reproductive age (WRA), which is not well described. MATERIALS AND METHODS: A population-based study was conducted using data from a survey of general practitioner (GP) encounters and state-wide hospital admissions in New South Wales (NSW). A list of 29 conditions and relevant diagnosis codes was used to identify autoimmune disease. Prevalence estimates and trends were calculated using population denominators for GP encounters for WRA in 2011-2015 and hospital admissions for WRA and pregnant women in 2013-2017. RESULTS: A total 31,065 GP encounters for WRA were identified and 607 (2.0%) reported an autoimmune disease, equivalent to 1.1 GP encounters per 10 WRA each year when extrapolating to NSW population figures. For WRA admitted to hospital, 2.6% had an autoimmune diagnosis recorded each year equivalent to a population prevalence of 0.5%. A total 477,243 births were identified, of which 4230 mothers (0.9%) had at least one autoimmune disease recorded during a 1-year pregnancy lookback period. Autoimmune disease prevalence among both pregnant women and WRA either attending GP or hospital increased, on average, 2-4% per year over the study period. CONCLUSIONS: A small, but potentially growing proportion of reproductive age and pregnant women have a diagnosed autoimmune disease, and this may impact their health outcomes.

Inequality in early childhood chronic health conditions requiring hospitalisation: A data linkage study of health service utilisation and costs.

BACKGROUND: The cost of socioeconomic inequality in health service use among Australian children with chronic health conditions is poorly understood. OBJECTIVES: To quantify the cost of socioeconomic inequality in health service use among Australian children with chronic health conditions. METHODS: Cohort study using a whole-of-population linked administrative data for all births in Queensland, Australia, between July 2015 and July 2018. Socioeconomic status was defined by an areas-based measure, grouping children into quintiles from most disadvantaged (Q1) to least disadvantaged (Q5) based on their postcode at birth. Study outcomes included health service utilisation (inpatient, emergency department, outpatient, general practitioner, specialist, pathology and diagnostic imaging services) and healthcare costs. RESULTS: Of the 238,600 children included in the analysis, 10.4% had at least one chronic health condition. Children with chronic health conditions in Q1 had higher rates of inpatient (6.6, 95% confidence interval [CI] 6.4, 6.7), emergency department (7.2, 95% CI 7.0, 7.5) and outpatient (20.3, 95% CI 19.4, 21.3) service use compared to children with chronic health conditions in Q5. They also had lower rates of general practitioner (37.5, 95% CI 36.7, 38.4), specialist (8.9, 95% CI 8.5, 9.3), pathology (10.7, 95% CI 10.2, 11.3), and diagnostic imaging (4.3, 95% CI 4.2,4.5) service use. Children with any chronic health condition in Q1 incurred lower median out-of-pocket fees than children in Q5 ($0 vs $741, respectively), lower median Medicare funding ($2710, vs $3408, respectively), and higher median public hospital funding ($31, 052 vs $23, 017, respectively). CONCLUSIONS: Children of most disadvantage are more likely to access public hospital provided services, which are accessible free of charge to patients. These children are less likely to access general practitioner, specialist, pathology and diagnostic imaging services; all of which are critical to the ongoing management of chronic health conditions, but often attract an out-of-pocket fee.

Prevalence of autoimmune conditions in pregnant women in a tertiary maternity hospital: A cross-sectional survey and maternity database review.

BACKGROUND: Autoimmune conditions are associated with adverse pregnancy and offspring outcomes; however, the prevalence in pregnant women is not well understood. Estimates based on administrative data alone may underestimate prevalence. METHODS: A cross-sectional survey of women attending a tertiary referral hospital for antenatal care in December 2018-February 2019 and review of the hospital's maternity database of women giving birth from October 2017-June 2018 to estimate autoimmune disease prevalence. RESULTS: A total of 400 women completed surveys (78% response rate) and 41 (10.3%) reported an autoimmune disease, most commonly Hashimoto's thyroiditis (2.8%) and psoriasis (2.5%). From the maternity database, 112 of 2756 women giving birth (4.1%) had a recorded autoimmune disease, most commonly Hashimoto's thyroiditis (1.3%) followed by coeliac disease, Graves' disease, and immune thrombocytopenic purpura (all 0.4%). CONCLUSION: Autoimmune disease prevalence in pregnant women is higher when self-reported and may be more common than previously reported using administrative data.

The accuracy of hospital discharge data in recording major congenital anomalies in Australia.

BACKGROUND: There has been increasing use of hospital discharge data to identify congenital anomalies, with limited information about the accuracy of these data. OBJECTIVES: To evaluate the accuracy of hospital discharge data in ascertaining major congenital anomalies in infants. METHODS: All liveborn infants with major congenital anomalies born between 2004 and 2009 in New South Wales, Australia were included. They were separated into two study groups: (a) infants identified from the Register of Congenital Conditions with a corresponding record in linked hospital discharge data; and (b) infants with a recorded congenital anomaly in hospital data, but without a register record. For the first group, we assessed agreement (concordant diagnoses) and the proportion of anomalies with discrepant diagnoses in each dataset. For the second group, we determined the number of anomalies recorded only in hospital data and applied specific conditions restricting to those recorded in the birth admission, excluding nonspecific diagnoses, or those with relevant surgical procedures to minimize potential false positives or over-reporting. RESULTS: The first study group included 9,346 infants with an average 84% agreement in the ascertainment of major anomalies between hospital and registry data, and >93% agreement for cardiac, abdominal wall, and gastrointestinal anomalies. Discrepant diagnoses occurred on average in 20% of cases from hospital data and 17% from registry data, and were slightly reduced with the use of diagnoses recorded only in tertiary pediatric hospitals. The second group included 25,893 infants where anomalies were only recorded in hospital data, most commonly skin and unspecified anomalies. Excluding unspecified cases, those only diagnosed at the birth admission and restricting to surgical procedures reduced over-reporting by up to 96%. CONCLUSIONS: Hospital discharge data provide an acceptable means to ascertain congenital anomalies, but with variable accuracy for different anomalies. Application of specific conditions and limited to surgical procedures improves the utility of using hospital discharge data to ascertain congenital anomalies.

A systematic review of the outcomes of false-positive results on newborn screening for congenital hypothyroidism.

OBJECTIVES: The potential of harm to infants or their parents from a false positive (FP) newborn screening (NBS) result for congenital hypothyroidism (CH) is often cited as an argument against lowering of screening thresholds for CH. This systematic review (SR) examines the evidence of harm and factors that possibly contribute. STUDY DESIGN: PRISMA guidelines were followed and the protocol was registered online (Prospero, ID CRD42019123950, 20 August 2019) before the search was conducted. Multiple electronic databases and grey literature were searched. Articles were included/excluded based on predetermined eligibility criteria. Included articles were appraised for quality, using the relevant Critical Appraisal Skills Program (CASP) tool. Data were extracted and results were tabulated and summarised as part of a narrative synthesis. RESULTS: A total of six studies met the inclusion criteria. All were qualitative and three were based on the same cohort. Studies were published between 1983 and 1996. CASP appraisals scored 2/6 studies as moderate quality and 4/6 as low quality. Studies reported that FP results on CH screening may cause initial stress for parents and poorly defined behavioural disturbance in a small number of children, though these effects were generally not long-lasting. Poor screening processes and inadequate communication with parents, increased the risk of harm to parents and children, from FP results. CONCLUSION: This SR found a small number of dated, qualitative studies of low to moderate quality, conducted soon after the initiation of NBS for CH. Conclusive evidence of the risks of harm from FP results and ways to mitigate harm, awaits further, well-designed studies.

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.

Association of Maternal Autoimmune Disease With Attention-Deficit/Hyperactivity Disorder in Children.

Importance: Maternal autoimmune disease has been associated with increased risk of neurodevelopmental disorders in offspring, but few studies have assessed the association with attention-deficit/hyperactivity disorder (ADHD). Objective: To examine the association between maternal autoimmune disease and ADHD within a population-based cohort and combine results in a subsequent systematic review and meta-analysis. Design, Setting, and Participants: A cohort study was conducted of singleton children born at term gestation (37-41 weeks) in New South Wales, Australia, from July 1, 2000, to December 31, 2010, and followed up until the end of 2014; and a systematic review evaluated articles from the MEDLINE, Embase, and Web of Science databases to identify all studies published before November 20, 2019. A total of 12 610 children exposed to maternal autoimmune disease were propensity score matched (1:4) to 50 440 unexposed children, for a total cohort of 63 050. A child was considered to have ADHD if they had (1) an authorization or filled prescription for stimulant treatment for ADHD or (2) a hospital diagnosis of ADHD. Children linked to a first ADHD event before 3 years of age were excluded. Data were analyzed from January 13 to April 20, 2020. Exposures: One or more maternal autoimmune diagnoses in linked hospital admission records between July 1, 2000, and December 31, 2012. Thirty-five conditions were considered together and individually. Main Outcomes and Measures: The main outcome was child ADHD identified from stimulant authorization or prescription data and diagnoses in linked hospital admission records. Multivariable Cox regression was used to assess the association between maternal autoimmune disease and ADHD adjusted for child sex. Pooled hazard ratios (HRs) were calculated using random-effects meta-analysis with inverse-variance weights for each exposure reported by 2 or more studies. Results: In the population-based cohort analysis, 831 718 singleton, term infants born to 831 718 mothers (mean [SD] age, 29.8 [5.6] years) were assessed. Of 12 767 infants (1.5%) who were linked to a maternal autoimmune diagnosis, 12 610 were propensity score matched to 50 440 control infants, for a total study cohort of 63 050 infants. In this cohort, any autoimmune disease was associated with ADHD in offspring (HR, 1.30; 95% CI 1.15-1.46), as was type 1 diabetes (HR, 2.23; 95% CI, 1.66-3.00), psoriasis (HR, 1.66; 95% CI, 1.02-2.70), and rheumatic fever or rheumatic carditis (HR, 1.75; 95% CI, 1.06-2.89). Five studies (including the present study) were included in the meta-analysis. Any autoimmune disease (2 studies: HR, 1.20; 95% CI, 1.03-1.38), type 1 diabetes (4 studies: HR, 1.53; 95% CI, 1.27-1.85), hyperthyroidism (3 studies: HR, 1.15; 95% CI, 1.06-1.26), and psoriasis (2 studies: HR, 1.31; 95% CI, 1.10-1.56) were associated with ADHD. Conclusions and Relevance: In this cohort study, maternal autoimmune diseases were associated with increased ADHD among children. These findings suggest possible shared genetic vulnerability between autoimmune disease and ADHD or a potential role for maternal immune activation in the expression of neurodevelopmental disorders in children. Future studies measuring disease activity, modifiers, and medication use are required to better understand the mechanisms underlying this association.

Association of elevated neonatal thyroid-stimulating hormone levels with school performance and stimulant prescription for attention deficit hyperactivity disorder in childhood.

Untreated severe newborn thyroid deficiency causes neurocognitive impairment; however, the impact of mild thyroid deficiency is not known. This study aimed to examine whether mildly elevated neonatal thyroid-stimulating hormone (TSH) levels are associated with poor school performance or stimulant prescription for attention deficit hyperactivity disorder (ADHD). This record-linkage study included 232,790 term-born infants in Australia with a TSH level below newborn screening threshold (< 15 mIU/L). Among our cohort, as TSH levels increased, the proportion of infants born low birthweight via caesarean section and with disadvantaged socioeconomic status increased. Multivariable logistic regression analysis showed that, compared with infants with 'normal' neonatal TSH level (< 5 mIU/L), those with neonatal TSH 10-15 mIU/L had an increased risk of being exempt from school testing (aOR 1.63 (95% CI 1.06-2.69)) or prescribed a stimulant for ADHD (aOR 1.57 (95% CI 1.10-2.24)), adjusted for perinatal and sociodemographic factors. Among a nested analysis of 460 sibling pairs, siblings with 'mildly elevated' TSH levels were more likely to be exempt from school tests compared with siblings with normal TSH levels (aOR 2.53, 95% CI 1.01-6.33).Conclusion: In this population cohort and sibling analysis, mildly elevated neonatal TSH levels were associated with being exempt from school testing due to significant or complex disability. What is Known: • Newborn screening for severe thyroid hormone deficiency has virtually eliminated congenital hypothyroidism-associated intellectual disability in developed countries. • The impact of mild thyroid hormone deficiency in infants is unclear. What is New: • Children with a mildly elevated neonatal TSH level below current newborn screening cut-offs have an increased likelihood of being exempt from school testing due to significant or complex disability compared with siblings and peers. This study includes a population-based and nested sibling analysis.

Neonatal Thyroxine, Maternal Thyroid Function, and Cognition in Mid-childhood in a US Cohort.

OBJECTIVE: Examine the associations of maternal thyroid hormones, maternal dietary information, and newborn T4 levels with cognitive outcomes in mid-childhood. METHODS: We studied 921 children born 1999-2003 at gestational age ≥ 34 weeks, who were participants in Project Viva, a prospective pre-birth cohort study in Massachusetts. We examined maternal dietary information, maternal thyroid hormone levels, and neonatal levels of T4. Research staff performed cognitive testing in mid-childhood (median age 7.7 years). RESULTS: We included 514 women with measured first trimester thyroid hormone concentrations (mean 10.2 weeks); 15% of women had a thyroid stimulating hormone (TSH) level ≥ 2.5 mU/L, and 71% were college graduates. Newborn T4 was collected from 375 infants (mean 17.6 µg/dl; SD 4.0), on day 2 (mean 1.9 days; SD 0.7) as part of the newborn screening program. Mean (SD) verbal and nonverbal IQ, memory, and motor scores of children were 113.2 (14.3), 107.1 (16.7), 17.1 (4.4), and 92.5 (16.6) points, respectively. In multivariable analysis, first trimester maternal thyroid function (total T3, total T4, free T4, thyroid stimulating hormone (TSH) or total thyroid peroxidase (TPO) antibody levels) or newborn T4 were not associated with any of the cognitive outcomes in mid-childhood after adjustment for sociodemographic and perinatal variables. CONCLUSIONS FOR PRACTICE: Maternal or neonatal thyroid hormone levels were not associated with cognitive outcomes in mid-childhood in this population with generally normal thyroid function. As we studied a highly educated cohort residing in an iodine-sufficient area, findings may not be generalizable.