Opioid analgesic exposure during the first trimester of pregnancy and the risk of major congenital malformations in infants: a systematic review and meta-analysis†.

BACKGROUND: Prescribed opioid analgesics are frequently used to manage pain in pregnancy. However, the available literature regarding the teratogenic potential of opioid use during pregnancy has not been systematically summarised. This systematic review and meta-analysis aimed to assess the quality of the evidence on these potential risks and calculate a pooled estimate of risk for any opioid analgesic and individual opioids. METHODS: We searched PubMed, Embase and CINAHL for published studies assessing the risk of major congenital malformations in infants following first-trimester exposure to opioid analgesics compared with a reference group, excluding studies examining opioid agonist therapy or illicit opioid use. We assessed the risk of bias using the Risk of Bias in Non-Randomised Studies of Intervention tool. We pooled adjusted risk estimates from studies rated at serious risk of bias or better in a random-effects meta-analysis. RESULTS: Of 12 identified studies, 11 were at high risk of bias (eight serious; three critical). Relative to unexposed infants, those exposed to any opioid use during the first trimester of pregnancy were not at an increased risk of major congenital malformations overall (relative risk 1.04, 95%CI 0.98-1.11); cardiovascular malformations (relative risk 1.07, 95%CI 0.96-1.20); or central nervous system malformations (relative risk 1.06, 95%CI 0.92-1.21). Raised risk estimates were observed for gastrointestinal malformations (relative risk 1.40, 95%CI 0.38-5.16) and cleft palate (relative risk 1.57, 95%CI 0.48-5.13) following any opioid exposure and atrial septal defects (relative risk 1.20, 95%CI 1.05-1.36) following codeine exposure. CONCLUSIONS: Although the meta-analysis did not indicate substantial increased risk for most malformations examined, this risk remains uncertain due to the methodological limitations of the included studies. Healthcare professionals and pharmaceutical regulators should be aware of the issues related to the quality of research in this field.

Antipsychotic use during pregnancy and risk of specific neurodevelopmental disorders and learning difficulties in children: a multinational cohort study.

Background: Antipsychotics are commonly prescribed to treat a range of psychiatric conditions in women of reproductive age and during pregnancy, including schizophrenia, bipolar disorder, anxiety, depression, autism spectrum disorder, and insomnia. This study aimed to evaluate whether children exposed to antipsychotic medication prenatally are at increased risk of specific neurodevelopmental disorders and learning difficulties. Methods: Our population-based cohort study used nationwide register data (1 January 2000-31 December 2020) on pregnant women diagnosed with a psychiatric disorder and their live-born singletons from Denmark, Finland, Iceland, Norway, and Sweden. Cox proportional hazard regression yielded propensity score-weighted hazard ratios (aHRs) and 95% confidence intervals (CIs) for risk of intellectual-, speech or language-, learning-developmental disorders, and a composite outcome of the listed disorders. We defined poor performance as scoring within the lowest quartile on national school tests in mathematics and language arts. We estimated propensity score-weighted risk ratios (aRRs) using Poisson regression. We analysed data from Denmark separately and pooled results using random effects meta-analysis. Findings: Among 213,302 children (median follow-up: 6.7 years), 11 626 (5.5%) were exposed to antipsychotics prenatally. Adjusted risk estimates did not suggest an increased risk of neurodevelopmental disorders: aHR of 1.06 (95% CI 0.94-1.20) for the composite outcome, or for poor academic performance: aRR of 1.04 (95% CI 0.91-1.18) in mathematics, and of 1.00 (95% CI 0.87-1.15) in language arts. Results were generally consistent across individual medications, trimesters of exposure, sibling- and sensitivity analyses. Interpretation: The findings of this large multinational cohort study suggest there is little to no increased risk of child neurodevelopmental disorders or learning difficulties after prenatal exposure to antipsychotics. Our findings can assist clinicians and women managing mental illness during pregnancy. Funding: This study was funded by the NordForsk Nordic Program on Health and Welfare (Nordic Pregnancy Drug Safety Studies, project No. 83539), by the Research Council of Norway (International Pregnancy Drug Safety Studies, project No. 273366) and by the Research Council of Norway through its Centres of Excellence funding scheme (project No. 262700), and UNSW Scientia Programme Awards (PS46019, PS46019-A).

Geographic variation in sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide-1 receptor agonist use in people with type 2 diabetes in New South Wales, Australia.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and cardio-renal outcomes for people with type 2 diabetes (T2D). However, geographic and socio-economic variation in use is not well understood. METHODS: We identified 367 829 New South Wales residents aged ≥40 years who dispensed metformin in 2020 as a proxy for T2D. We estimated the prevalence of use of other glucose-lowering medicines among people with T2D and the prevalence of SGLT2i and GLP-1RA use among people using concomitant T2D therapy (i.e. metformin + another glucose-lowering medicine). We measured the prevalence by small-level geography, stratified by age group, and characterized by remoteness and socio-economic status. RESULTS: The prevalence of SGLT2i (29.7%) and GLP-1RA (8.3%) use in people with T2D aged 40-64 increased with geographic remoteness and in areas of greater socio-economic disadvantage, similar to other glucose-lowering medicines. The prevalence of SGLT2i (55.4%) and GLP-1RA (15.4%) among people using concomitant T2D therapy varied across geographic areas, with lower SGLT2i use in more disadvantaged areas and localized areas of high GLP-1RA use (2.5 times the median). Compared with people aged 40-64 years, the prevalence of SGLT2i and GLP-1RA use was lower in older age groups, but with similar patterns of variation across geographic areas. CONCLUSIONS: The prevalence of SGLT2i and GLP-1RA use varied by geography, probably reflecting a combination of system- and prescriber-level factors. Socio-economic variation in GLP-1RA use was overshadowed by localized patterns of prescribing. Continued monitoring of variation can help shape interventions to optimize use among people who would benefit the most.

The burden of prenatal and early life maternal substance use among children at risk of maltreatment: A systematic review.

ISSUES: Although maternal substance use is a known risk factor for child maltreatment, evidence on the scale of substance use is needed to inform prevention responses. This systematic review synthesised prevalence estimates of maternal substance use during pregnancy and early life among children at risk of maltreatment. Ovid, Pubmed, CINAHL, PsychInfo and ProQuest databases were searched. We included observational studies that sampled children at risk of maltreatment in high-income countries and reported information on maternal substance use during pregnancy and/or the child's first year of life. We extracted study characteristics and data to calculate prevalence, assessed risk of bias and conducted a narrative synthesis; there were insufficient comparable populations or outcomes to quantitatively synthesise results. KEY FINDINGS: Thirty five of 14,084 titles were included. Fifteen studies had adequately sized and representative samples to estimate prevalence. Maternal substance use prevalence ranged from 2.4% to 40.6%. Maternal substance use was highest among infants referred to child protection at birth (40.6%) and children in out-of-home care (10.4% to 37.2%). Prevalence was higher when studies defined substance use more broadly and when maternal substance use was ascertained from both child and mother records. IMPLICATIONS: Supportive, coordinated responses to maternal substance use are needed from health and child protection services, spanning alcohol and other drug treatment, antenatal and postnatal care. CONCLUSIONS: Prenatal and early life maternal substance use is common among child maltreatment populations, particularly among younger children and those with more serious maltreatment.

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

BACKGROUND AND OBJECTIVES: Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. METHODS: We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. RESULTS: Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. DISCUSSION: Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

Prevalence and Persistence of Prescription Opioid Use Following Hospital Discharge After Childbirth: An Australian Population-Based Cohort Study.

BACKGROUND: Opioid analgesics are used for acute postpartum pain relief but carry risks, including persistent long-term opioid use. Our primary objective was to estimate the prevalence of persistent use following hospital discharge after childbirth. METHODS: We conducted a population-based cohort study of women discharged from public or private hospitals in New South Wales, Australia, between 2012 and 2018 following vaginal birth (VB) or cesarean delivery (CD). We used linked hospitalization and medicine dispensing data to calculate the prevalence of opioid use within 14 days of hospital discharge for childbirth using an external estimate of the total number of hospital admissions for childbirth per year as the denominator. Among women dispensed an opioid postdischarge, we estimated the prevalence of persistent use defined as ≥3 dispensings between 30- and 365-days postdischarge. To calculate the odds of persistent opioid use, we performed a series of logistic regressions each including a single characteristic of interest. Included characteristics were maternal and birth characteristics, maternal medical conditions, prior use of certain medicines, and the initial opioid dispensed following discharge for childbirth. RESULTS: The final cohort comprised of 38,832 women who were dispensed an opioid in the 14 days following discharge after childbirth. Between 2012 and 2018, the prevalence of opioid use was increased following CD (public hospital 16.6%-21.0%; private hospital 9.8%-19.5%) compared with VB (public hospital 1.5%-1.5%; private hospital 1.2%-1.4%) and was higher following discharge from public hospitals compared with private. The most commonly dispensed opioids following discharge for childbirth were oxycodone (44.8%; 95% confidence interval [CI], 44.3-45.3), codeine (42.1%; 95% CI, 41.6-42.6), and tramadol (12.9%; 95% CI, 12.6-13.2). Among women dispensed an opioid, the prevalence of persistent opioid use was 5.4% (95% CI, 5.1-5.6). This prevalence was 11.4% (95% CI, 10.5-12.3) following a VB as compared with 4.3% (95% CI, 4.1-4.6) among those who underwent a CD ( P < .001). Characteristics associated with persistent opioid use included smoking during pregnancy, age <25 years, living in remote areas, discharged from a public hospital, history of opioid use disorder, other substance use disorder, mental health diagnosis, or prior use of prescription opioids, nonopioid analgesics, or benzodiazepines. CONCLUSIONS: The results of this cohort study indicate that Australian women have a higher prevalence of opioid use following CD compared to VB. One in 19 women dispensed an opioid postdischarge used opioids persistently. Careful monitoring of opioid therapy following childbirth is warranted, particularly among women with characteristics we identified as high risk for persistent opioid use.

Risk for Congenital Anomalies in Children Conceived With Medically Assisted Fertility Treatment : A Population-Based Cohort Study.

BACKGROUND: More than 2 million children are conceived annually using assisted reproductive technologies (ARTs), with a similar number conceived using ovulation induction and intrauterine insemination (OI/IUI). Previous studies suggest that ART-conceived children are at increased risk for congenital anomalies (CAs). However, the role of underlying infertility in this risk remains unclear, and ART clinical and laboratory practices have changed drastically over time, particularly there has been an increase in intracytoplasmic sperm injection (ICSI) and cryopreservation. OBJECTIVE: To investigate the role of underlying infertility and fertility treatment on CA risks in the first 2 years of life. DESIGN: Propensity score-weighted population-based cohort study. SETTING: New South Wales, Australia. PARTICIPANTS: 851 984 infants (828 099 singletons and 23 885 plural children) delivered between 2009 and 2017. MEASUREMENTS: Adjusted risk difference (aRD) in CAs of infants conceived through fertility treatment compared with 2 naturally conceived (NC) control groups-those with and without a parental history of infertility (NC-infertile and NC-fertile). RESULTS: The overall incidence of CAs was 459 per 10 000 singleton births and 757 per 10 000 plural births. Compared with NC-fertile singleton control infants (n = 747 018), ART-conceived singleton infants (n = 31 256) had an elevated risk for major genitourinary abnormalities (aRD, 19.0 cases per 10 000 births [95% CI, 2.3 to 35.6]); the risk remained unchanged (aRD, 22 cases per 10 000 births [CI, 4.6 to 39.4]) when compared with NC-infertile singleton control infants (n = 36 251) (that is, after accounting for parental infertility), indicating that ART remained an independent risk. After accounting for parental infertility, ICSI in couples without male infertility was associated with an increased risk for major genitourinary abnormalities (aRD, 47.8 cases per 10 000 singleton births [CI, 12.6 to 83.1]). There was some suggestion of increased risk for CAs after fresh embryo transfer, although estimates were imprecise and inconsistent. There were no increased risks for CAs among OI/IUI-conceived infants (n = 13 574). LIMITATIONS: This study measured the risk for CAs only in those children who were born at or after 20 weeks' gestation. Observational study design precludes causal inference. Many estimates were imprecise. CONCLUSION: Patients should be counseled on the small increased risk for genitourinary abnormalities after ART, particularly after ICSI, which should be avoided in couples without problems of male infertility. PRIMARY FUNDING SOURCE: Australian National Health and Medical Research Council.

Agreement of acute serious events recorded across datasets using linked Australian general practice, hospital, emergency department and death data: implications for research and surveillance.

Introduction: Understanding the level of recording of acute serious events in general practice electronic health records (EHRs) is critical for making decisions about the suitability of general practice datasets to address research questions and requirements for linking general practice EHRs with other datasets. Objectives: To examine data source agreement of five serious acute events (myocardial infarction, stroke, venous thromboembolism (VTE), pancreatitis and suicide) recorded in general practice EHRs compared with hospital, emergency department (ED) and mortality data. Methods: Data from 61 general practices routinely contributing data to the MedicineInsight database was linked with New South Wales administrative hospital, ED and mortality data. The study population comprised patients with at least three clinical encounters at participating general practices between 2019 and 2020 and at least one record in hospital, ED or mortality data between 2010 and 2020. Agreement was assessed between MedicineInsight diagnostic algorithms for the five events of interest and coded diagnoses in the administrative data. Dates of concordant events were compared. Results: The study included 274,420 general practice patients with at least one record in the administrative data between 2010 and 2020. Across the five acute events, specificity and NPV were excellent (>98%) but sensitivity (13%-51%) and PPV (30%-75%) were low. Sensitivity and PPV were highest for VTE (50.9%) and acute pancreatitis (75.2%), respectively. The majority (roughly 70-80%) of true positive cases were recorded in the EHR within 30 days of administrative records. Conclusion: Large proportions of events identified from administrative data were not detected by diagnostic algorithms applied to general practice EHRs within the specific time period. EHR data extraction and study design only partly explain the low sensitivities/PPVs. Our findings support the use of Australian general practice EHRs linked to hospital, ED and mortality data for robust research on the selected serious acute conditions.

Trends in use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in Australia in the era of increased evidence of their cardiovascular benefits (2014-2022).

PURPOSE: To investigate trends in SGLT2i and GLP-1RA use in Australia in the era of increased evidence of their cardiovascular benefits. METHODS: We used national dispensing claims for a 10% random sample of Australians to estimate the number of prevalent and new users (no dispensing in the prior year) of SGLT2i or GLP-1RA per month from January 2014 to July 2022. We assessed prescriber specialty and prior use of other antidiabetic and cardiovascular medicines as a proxy for evidence of type 2 diabetes (T2D) and cardiovascular conditions, respectively. RESULTS: We found a large increase in the number of prevalent users (216-fold for SGLT2i; 11-fold for GLP-1RA); in July 2022 approximately 250,000 Australians were dispensed SGLT2i and 120,000 GLP-1RA. Most new users of SGLT2i or GLP-1RA had evidence of both T2D and cardiovascular conditions, although from 2022 onwards, approximately one in five new users of SGLT2i did not have T2D. The proportion of new users initiating SGLT2i by cardiologists increased after 2021, reaching 10.0% of initiations in July 2022. Among new users with evidence of cardiovascular conditions, empagliflozin was the most commonly prescribed SGLT2i, while dulaglutide or semaglutide was the most common GLP-1RA. CONCLUSION: SGLT2i and GLP-1RA use is increasing in Australia, particularly in populations with higher cardiovascular risk. The increased use of SGLT2i among people without evidence of T2D suggests that best-evidence medicines are adopted in Australia across specialties, aligning with new evidence and expanding indications.

Trends in smoking during pregnancy stratified by the use of opioid agonist therapy and the contribution of smoking to poor outcome in neonates prenatally exposed to opioid agonist treatment.

High rates of cigarette smoking have been observed in pregnant women on opioid agonist therapy (OAT). However, it is unclear if these rates have changed overtime in line with the general population and the degree to which smoking contributes to poor outcomes in neonates born to women on OAT. Women who gave birth in Western Australia (WA) between 2003 and 2018 were identified from whole-population midwives records. Linked records were used to identify women who had been dispensed OAT during pregnancy and those who had smoking during pregnancy. Temporal changes in smoking during pregnancy were examined for women on OAT (n = 1059) and women not on OAT (n = 397,175) using Joinpoint regression. In women treated with OAT during pregnancy, neonatal outcomes were compared between smoking and non-smoking women using generalised linear models. During the study period, 76.3% of women on OAT smoked during pregnancy compared with 12.0% of the general population. There was a decrease in the prevalence of smoking during pregnancy among women not on OAT (APC: - 5.7, 95%CI: - 6.3, - 5.2), but not in women on OAT (APC: 0.8, 95%CI: - 0.4, 2.1). For women receiving OAT, smoking was associated with an increased odds of low birth weight (OR: 1.57, 95%CI: 1.06, 2.32) and neonatal abstinence syndrome (OR: 1.34, 95%CI: 1.01, 1.78) compared with non-smoking. Despite reductions in the prevalence of smoking during pregnancy in the general population, similar reductions have not occurred in pregnant women on OAT. The high prevalence of smoking in pregnant women on OAT is contributing to poor neonatal outcomes.

Mortality during and after specialist alcohol and other drug treatment: Variation in rates according to principal drug of concern and treatment modality.

INTRODUCTION: For people accessing treatment for problems with drugs other than opioids, little is known about the relationship between treatment and mortality risk, nor how mortality risk varies across treatment modalities. We addressed these evidence gaps by determining mortality rates during and after treatment for people accessing a range of treatment modalities for several drugs of concern. METHODS: We conducted a cohort study using linked data on publicly funded specialist alcohol or other drug treatment service use and mortality for people receiving treatment in New South Wales between January 2012 and December 2018. We calculated and compared during-treatment and post-treatment crude mortality rates and age- and sex-standardised mortality rates, separately for each principal drug of concern and modality. RESULTS: Over the study period, 45,026 people accessed treatment for problems with alcohol, 26,407 for amphetamine-type stimulants, 23,047 for cannabinoids and 21,556 for opioids. People treated for alcohol or opioid problems had higher crude mortality rates (1.48, 1.91, 1.09 per 100 person years, respectively) than those with problems with amphetamine-type stimulants or cannabinoids (0.46, 0.30 per 100 person years, respectively). Mortality rates differed according to treatment status and modality only among people with alcohol or opioid problems. DISCUSSION AND CONCLUSIONS: The observed variation in mortality rates indicates there is scope to reduce mortality among people accessing treatment with alcohol or opioid problems. Future research on mortality among people accessing drug and alcohol treatment should account for the variation in mortality by drug of concern and treatment modality.

Comparative effect of varenicline and nicotine patches on preventing repeat cardiovascular events.

OBJECTIVE: To determine the comparative effectiveness of postdischarge use of varenicline versus prescription nicotine replacement therapy (NRT) patches for the prevention of recurrent cardiovascular events and mortality and whether this association differs by sex. METHODS: Our cohort study used routinely collected hospital, pharmaceutical dispensing and mortality data for residents of New South Wales, Australia. We included patients hospitalised for a major cardiovascular event or procedure 2011-2017, who were dispensed varenicline or prescription NRT patches within 90day postdischarge. Exposure was defined using an approach analogous to intention to treat. Using inverse probability of treatment weighting with propensity scores to account for confounding, we estimated adjusted HRs for major cardiovascular events (MACEs), overall and by sex. We fitted an additional model with a sex-treatment interaction term to determine if treatment effects differed between males and females. RESULTS: Our cohort of 844 varenicline users (72% male, 75% <65 years) and 2446 prescription NRT patch users (67% male, 65% <65 years) were followed for a median of 2.93 years and 2.34 years, respectively. After weighting, there was no difference in risk of MACE for varenicline relative to prescription NRT patches (aHR 0.99, 95% CI 0.82 to 1.19). We found no difference (interaction p=0.098) between males (aHR 0.92, 95% CI 0.73 to 1.16) and females (aHR 1.30, 95% CI 0.92 to 1.84), although the effect among females deviated from the null. CONCLUSION: We found no difference between varenicline and prescription NRT patches in the risk of recurrent MACE. These results should be considered when determining the most appropriate choice of smoking cessation pharmacotherapy.

Patterns of attention deficit hyperactivity disorder medicine use in the era of new non-stimulant medicines: A population-based study among Australian children and adults (2013-2020).

BACKGROUND AND AIMS: New therapeutic options such as lisdexamfetamine and guanfacine have recently become available for the treatment of attention deficit hyperactivity disorder. We described contemporary patterns of attention deficit hyperactivity disorder medicine use among children, adolescents and adults in Australia. METHODS: This population-based study used dispensing data for a 10% random sample of Australian residents between July 2012 and December 2020. We estimated the annual prevalence and incidence of attention deficit hyperactivity disorder medicines, second-line guanfacine use and examined concurrent medicine use of both stimulants and non-stimulants. We followed incident users for up to 5 years and analysed treatment persistence using a novel proportion of people covered method. Analyses were stratified by attention deficit hyperactivity disorder medicine, sex and age group; young children (0-5 years), children (6-12 years), adolescents (13-17 years), young adults (18-24 years) and adults (⩾25 years). RESULTS: We observed a twofold increase in the overall prevalence of attention deficit hyperactivity disorder medicine use between 2013 and 2020, from 4.9 to 9.7 per 1000 persons. Incident use also increased across all age groups and both sexes, with the most pronounced increases among adolescent females (from 1.4 to 5.3 per 1000 persons). Stimulant treatment persistence after 5 years was highest among those initiating treatment as young children (64%) and children (69%) and lowest among those initiating treatment in adolescence (19%). Concurrent use of stimulants and non-stimulants was more common among males and younger age groups. Most children (87%) initiating guanfacine had prior dispensings of attention deficit hyperactivity disorder medicines. CONCLUSION: We observed increasing attention deficit hyperactivity disorder medicine use in Australia, especially among young females. Nevertheless, treatment rates remain lower than the estimated prevalence of attention deficit hyperactivity disorder across all subpopulations. Poor long-term treatment persistence in adolescence may warrant improved clinical monitoring of attention deficit hyperactivity disorder in patients transitioning from paediatric to adult care. Reassuringly, use of newly approved guanfacine appeared to be in accordance with guidelines among children.

The association between psychostimulant use in pregnancy and adverse maternal and neonatal outcomes: results from a distributed analysis in two similar jurisdictions.

BACKGROUND: Conflicting evidence suggests a possible association between use of prescribed psychostimulants during pregnancy and adverse perinatal outcomes. METHODS: We conducted population-based cohort studies including pregnancies conceived between April 2002 and March 2017 (Ontario, Canada; N = 554 272) and January 2003 to April 2011 [New South Wales (NSW), Australia; N = 139 229]. We evaluated the association between exposure to prescription amphetamine, methylphenidate, dextroamphetamine or lisdexamfetamine during pregnancy and pre-eclampsia, placental abruption, preterm birth, low birthweight, small for gestational age and neonatal intensive care unit admission. We used inverse probability of treatment weighting based on propensity scores to balance measured confounders between exposed and unexposed pregnancies. Additionally, we restricted the Ontario cohort to social security beneficiaries where supplementary confounder information was available. RESULTS: In Ontario and NSW respectively, 1360 (0.25%) and 146 (0.10%) pregnancies were exposed to psychostimulants. Crude analyses indicated associations between exposure and nearly all outcomes [OR range 1.15-2.16 (Ontario); 0.97-2.20 (NSW)]. Nearly all associations were attenuated after weighting. Pre-eclampsia was the exception: odds remained elevated in the weighted analysis of the Ontario cohort (OR 2.02, 95% CI 1.42-2.88), although some attenuation occurred in NSW (weighted OR 1.50, 95% CI 0.77-2.94) and upon restriction to social security beneficiaries (weighted OR 1.24, 95% CI 0.64-2.40), and confidence intervals were wide. CONCLUSIONS: We observed higher rates of outcomes among exposed pregnancies, but the attenuation of associations after adjustment and likelihood of residual confounding suggests psychostimulant exposure is not a major causal factor for most measured outcomes. Our findings for pre-eclampsia were inconclusive; exposed pregnancies may benefit from closer monitoring.

Most common principal diagnoses assigned to Australian emergency department presentations involving alcohol use: a multi-centre study.

OBJECTIVES: Alcohol is the most widely consumed psychoactive substance in Australia and the consequences of alcohol consumption have enormous personal and social impacts. This study aimed to describe the principal diagnoses of emergency department (ED) presentations involving alcohol use in the previous 12 hours at eight hospitals in Victoria and the Australian Capital Territory, Australia. METHODS: Twelve months' data (1 July 2018 - 30 June 2019) were collected from eight EDs, including demographics, ICD-10 codes, hospital location and self-reported drinking in the preceding 12 hours. The ten most common ICD-10 discharge codes were analysed based on age, sex and hospital geographic area. RESULTS: ICD codes pertaining to mental and behavioural disorders due to alcohol use accounted for the highest proportion in most EDs. Suicide ideation/attempt was in the five highest ICD codes for all but one hospital. It was the second most common alcohol-related presentation for both males and females. CONCLUSIONS: Alcohol plays a major role in a range of presentations, especially in relation to mental health and suicide. IMPLICATIONS FOR PUBLIC HEALTH: The collection of alcohol involvement in ED presentations represents a major step forward in informing the community about the burden of alcohol on their health resources.

Uptake of prescription smoking cessation pharmacotherapies after hospitalization for major cardiovascular disease.

AIMS: We determined the prevalence of prescription smoking cessation pharmacotherapy (SCP) use after hospitalization for major cardiovascular disease (MCD) among people who smoke and whether this varies by sex. METHODS AND RESULTS: We conducted a population-based cohort study including all people hospitalized in New South Wales, Australia, between July 2013 and December 2018 (2017 for private hospitals) with an MCD diagnosis. For patients who also had a diagnosis of current tobacco use, we used linked pharmaceutical dispensing records to identify prescription SCP dispensings within 90 days post-discharge. We determined the proportion who were dispensed an SCP within 90 days, overall and by type of SCP. We used logistic regression to estimate the odds of females being dispensed an SCP relative to males. Of the 150 758 patients hospitalized for an MCD, 20 162 (13.4%) had a current tobacco use diagnosis, 31% of whom were female. Of these, 11.3% (12.4% of females, 10.9% of males) received prescription SCP within 90 days post-discharge; 3.0% were dispensed varenicline, and 8.3% were dispensed nicotine replacement therapy patches. Females were more likely than males to be dispensed a prescription SCP [odds ratio (OR) 1.16, 95% confidence interval (CI) 1.06-1.27)]; however, this was not maintained after adjusting for potential confounders (adjusted OR 1.04, 95% CI 0.94-1.15). CONCLUSION: Very few females and males who smoke use prescription SCPs after hospitalization for an MCD. The use of varenicline, the SCP with the highest efficacy, was particularly low. This represents a missed opportunity to increase smoking cessation in this high-risk population, thereby reducing their risk of recurrent cardiovascular events.

Children's Relative Age and Medicine Treatment for Attention-Deficit/Hyperactivity Disorder Across Australian Jurisdictions with Different School Enrolment Policies.

Background: Children who are relatively young for their school grade are more likely to receive treatment for attention-deficit/hyperactivity disorder (ADHD). It is unclear whether the phenomenon also exists across Australia or is impacted by the school enrolment policy in place. Objective: We evaluated the association between children's relative age and initiation of ADHD medicines across Australian jurisdictions with different school enrolment policies and rates of delayed school entry. Methods: We used Australia-wide dispensing data for a 15% random sample of children 4-9 years of age in 2013-2017 to create a nationwide cohort. Due to high rates of delayed school entry in New South Wales (NSW), we used linked prescribing and education data for a cohort of NSW residents starting school in 2009 and 2012. We estimated incidence rate ratios (IRRs) for ADHD medicine across children's birth month, sex, and jurisdiction. We used asthma medicines as a negative control. Results: For girls, we observed a relative age effect in three out of five jurisdictions, with an IRR ranging from 1.3 to 2.8, comparing the youngest versus oldest birth month thirds. We observed more modest effects among boys, ranging from null to 1.5-fold. In NSW, the relatively youngest boys were less likely to initiate stimulant medicines than the oldest (IRR = 0.5, 95% confidence interval 0.29-0.78). We did not observe a relative age effect for initiation of asthma medicines. Conclusions: In jurisdictions with low rates of delayed entry, relatively young children were more likely to initiate ADHD medicines than their older classmates. We observed the inverse association in NSW where delayed entry was highest, likely reflecting the characteristics and needs of children who delay school entry for 1 year and become the oldest children in the grade. Increased awareness around children's maturity differences and school readiness may enhance appropriate diagnosis and treatment of ADHD.

Differences in the pre-hospital management of women and men with stroke by emergency medical services in New South Wales.

OBJECTIVES: To examine whether pre-hospital emergency medical service care differs for women and men subsequently admitted to hospital with stroke. DESIGN, SETTING, PARTICIPANTS: Population-based cohort study; analysis of linked Admitted Patient Data Collection and NSW Ambulance data for people admitted to New South Wales hospitals with a principal diagnosis of stroke at separation, 1 July 2005 - 31 December 2018. MAIN OUTCOME MEASURES: Emergency medical service assessments, protocols, and management for patients subsequently diagnosed with stroke, by sex. RESULTS: Of 202 231 people hospitalised with stroke (mean age, 73 [SD, 14] years; 98 599 women [51.0%]), 101 357 were conveyed to hospital by ambulance (50.1%). A larger proportion of women than men travelled by ambulance (52.4% v 47.9%; odds ratio [OR], 1.09; 95% CI, 1.07-1.11), but time between the emergency call and emergency department admission was similar for both sexes. The likelihood of being assessed as having a stroke (adjusted OR [aOR], 0.97; 95% CI, 0.93-1.01) or subarachnoid haemorrhage (aOR, 1.22; 95% CI, 0.73-2.03) was similar for women and men, but women under 70 years of age were less likely than men to be assessed as having a stroke (aOR, 0.89; 95% CI, 0.82-0.97). Women were more likely than men to be assessed by paramedics as having migraine, other headache, anxiety, unconsciousness, hypertension, or nausea. Women were less likely than men to be managed according to the NSW Ambulance pre-hospital stroke care protocol (aOR, 0.95; 95% CI, 0.92-0.97), but the likelihood of basic pre-hospital care was similar for both sexes (aOR, 1.01; 95% CI, 0.99-1.04). CONCLUSION: Our large population-based study identified sex differences in pre-hospital management by emergency medical services of women and men admitted to hospital with stroke. Paramedics should receive training that improves the recognition of stroke symptoms in women.