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.

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.

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.

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.

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.

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.

Population-wide contribution of medically assisted reproductive technologies to overall births in Australia: temporal trends and parental characteristics.

STUDY QUESTION: In a country with supportive funding for medically assisted reproduction (MAR) technologies, what is the proportion of MAR births over-time? SUMMARY ANSWER: In 2017, 6.7% of births were conceived by MAR (4.8% ART and 1.9% ovulation induction (OI)/IUI) with a 55% increase in ART births and a stable contribution from OI/IUI births over the past decade. WHAT IS KNOWN ALREADY: There is considerable global variation in utilization rates of ART despite a similar infertility prevalence worldwide. While the overall contribution of ART to national births is known in many countries because of ART registries, very little is known about the contribution of OI/IUI treatment or the socio-demographic characteristics of the parents. Australia provides supportive public funding for all forms of MAR with no restrictions based on male or female age, and thus provides a unique setting to investigate the contribution of MAR to national births as well as the socio-demographic characteristics of parents across the different types of MAR births. STUDY DESIGN, SIZE, DURATION: This is a novel population-based birth cohort study of 898 084 births using linked ART registry data and administrative data including birth registrations, medical services, pharmaceuticals, hospital admissions and deaths. Birth (a live or still birth of at least one baby of ≥400 g birthweight or ≥20 weeks' gestation) was the unit of analysis in this study. Multiple births were considered as one birth in our analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included a total of 898 084 births (606 488 mothers) in New South Wales and the Australian Capital Territory, Australia 2009-2017. We calculated the prevalence of all categories of MAR-conceived births over the study period. Generalized estimating equations were used to examine the association between parental characteristics (parent's age, parity, socio-economic status, maternal country of birth, remoteness of mother's dwelling, pre-existing medical conditions, smoking, etc.) and ART and OI/IUI births relative to naturally conceived births. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of MAR births increased from 5.1% of all births in 2009 to 6.7% in 2017, representing a 30% increase over the decade. The proportion of OI/IUI births remained stable at around 2% of all births, representing 32% of all MAR births. Over the study period, ART births conceived by frozen embryo-transfer increased nearly 3-fold. OI/IUI births conceived using clomiphene citrate decreased by 39%, while OI/IUI births conceived using letrozole increased 56-fold. Overall, there was a 55% increase over the study period in the number of ART-conceived births, rising to 56% of births to mothers aged 40 years and older. In 2017, almost one in six births (17.6%) to mothers aged 40 years and over were conceived using ART treatment. Conversely, the proportion of OI/IUI births was similar across different mother's age groups and remained stable over the study period. ART children, but not OI/IUI children, were more likely to have parents who were socio-economically advantaged compared to naturally conceived children. For example, compared to naturally conceived births, ART births were 16% less likely to be born to mothers who live in the disadvantaged neighbourhoods after accounting for other covariates (adjusted relative risk (aRR): 0.84 [95% CI: 0.81-0.88]). ART- or OI/IUI-conceived children were 25% less likely to be born to immigrant mothers than births after natural conception (aRR: 0.75 [0.74-0.77]). LIMITATIONS, REASONS FOR CAUTION: The social inequalities that we observed between the parents of children born using ART and naturally conceived children may not directly reflect disparities in accessing fertility care for individuals seeking treatment. WIDER IMPLICATIONS OF THE FINDINGS: With the ubiquitous decline in fertility rates around the world and the increasing trend to delay childbearing, this population-based study enhances our understanding of the contribution of different types of MARs to population profiles among births in high-income countries. The parental socio-demographic characteristics of MAR-conceived children differ significantly from naturally conceived children and this highlights the importance of accounting for such differences in studies investigating the health and development of MAR-conceived children. STUDY FUNDING/COMPETING INTEREST(S): This study was funded through Australian National Health and Medical Research Council (NHMRC) grant: APP1127437. G.M.C. is an employee of The University of New South Wales (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The NPESU manages the Australian and New Zealand Assisted Reproduction Database with funding support from the Fertility Society of Australia and New Zealand. C.V. is an employee of The University of New South Wales (UNSW), Director of Clinical Research of IVFAustralia, Member of the Board of the Fertility Society of Australia and New Zealand, and Member of Research Committee of School of Women's and Children's Health, UNSW. C.V. reports grants from Australian National Health and Medical Research Council (NHMRC), and Merck KGaA. C.V. reports consulting fees, and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript, writing or educational events or attending meeting or travel from Merck, Merck Sparpe & Dohme, Ferring, Gedon-Richter and Besins outside this submitted work. C.V. reported stock or stock options from Virtus Health Limited outside this submitted work. R.J.N. is an employee of The University of Adelaide, and Chair DSMC for natural therapies trial of The University of Hong Kong. R.J.N. reports grants from NHMRC. R.J.N. reports lecture fees and support for attending or travelling for lecture from Merck Serono which is outside this submitted work. L.R.J. is an employee of The UNSW and Foundation Director of the Centre for Big Data Research in Health at UNSW Sydney. L.R.J. reports grants from NHMRC. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Prescription opioid use in Australian women of reproductive age: Implications for unplanned pregnancies.

AIMS: To examine trends in the prevalence and incidence of prescription opioid analgesic use in Australian women of reproductive age and to estimate the number of calendar months each year that women were dispensed opioids. METHODS: We conducted a retrospective cross-sectional study involving women aged 15-44 years using pharmaceutical dispensing claims for a 10% random sample of Australians. For the period 2013-2020, we calculated the annual prevalence and incidence of opioid analgesic dispensing per 100 (%) population by opioid type and age group. We also estimated the total number of calendar months that women were dispensed at least 1 opioid each year. RESULTS: The prevalence of opioid use decreased from 12.8% in 2013 to 11.3% in 2020, representing a relative decrease of 11.6% (95% confidence interval 10.7, 12.6%). The incidence of opioid use decreased from 10.3% in 2014 to 8.3% in 2020, representing a relative decrease of 18.6% (95% confidence interval 17.6, 19.6%). Codeine in combination products, followed by oxycodone and tramadol, were the most prevalent opioids. Prevalence and incidence of opioid use were lowest in women aged 15-19 years and the highest in women 30 years and above. Among all women dispensed opioids, 72.7% were dispensed an opioid in only 1 month each year. CONCLUSION: Prescription opioid use remains common, although decreasing, among women of reproductive age in Australia. However, it is reassuring that the majority of opioid use in this population is short term.

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.

Sex differences in emergency medical services management of patients with myocardial infarction: analysis of routinely collected data for over 110,000 patients.

Emergency medical services (EMS) activation is an integral component in managing individuals with myocardial infarction (MI). EMS play a crucial role in early MI symptom recognition, prompt transport to percutaneous coronary intervention centres and timely administration of management. The objective of this study was to examine sex differences in prehospital EMS care of patients hospitalized with Ml using data from a retrospective population-based cohort study of linked health administrative data for people with a hospital diagnosis of MI in Australia (2001-18).

The Comparative Effectiveness of Varenicline and Nicotine Patches for Smoking Abstinence During Pregnancy: Evidence From a Population-based Cohort Study.

INTRODUCTION: In the general population, varenicline is consistently shown to be more efficacious for smoking cessation than nicotine replacement therapy (NRT). Current clinical guidelines for the management of smoking during pregnancy recommend against the use of varenicline, whilst supporting the use of NRT. However, little is known about the comparative effectiveness of these smoking cessation therapies among pregnant women. AIMS AND METHODS: Routinely-collected records of all births in two Australian States during 2011 and 2012 were used to create a population-based cohort of women who smoked during the first half of pregnancy. Pharmaceutical dispensing data were used to identify varenicline and nicotine patch dispensings in the first half of pregnancy. Propensity score matching was used to account for the potentially different distribution of confounding factors between the treatment groups. The outcome was defined as smoking abstinence during the second half of pregnancy. RESULTS: After propensity score-matching, our cohort comprised 60 women who used varenicline and 60 who used nicotine patches during the first half of pregnancy. More varenicline users (33.3%, 95% CI: 21.7%-46.7%) quit smoking than nicotine patch users (13.3%, 95% CI: 5.9%-24.6%). The adjusted rate difference was 24.2% (95% CI: 10.2%-38.2%) and the adjusted relative risk was 2.8 (95% CI: 1.4-5.7). CONCLUSIONS: Varenicline was almost three times more effective than nicotine patches in assisting pregnant women to quit smoking. Further studies are needed to corroborate our results. Together with data on the safety of varenicline during pregnancy, evidence regarding the relative benefit of varenicline and NRT during pregnancy important for informing clinical decisions for pregnant smokers. IMPLICATIONS: This study is the first to measure the comparative effectiveness of varenicline and nicotine patches during pregnancy - women using varenicline were almost three times as likely to quit smoking than those using nicotine patches. This study addressed a clinically important question using an observational study, noting that there is an absence of evidence from randomized controlled trials because of the ethical issues associated with including pregnant women in clinical trials of medicines of unknown safety.

Medications used disproportionately during pregnancy: Priorities for research on the risks and benefits of medications when used during pregnancy.

PURPOSE: To identify medications used disproportionately more or less among pregnant women relative to women of childbearing age. METHODS: Medication use among pregnant women in New South Wales, Australia was identified using linked perinatal and pharmaceutical dispensing data from 2006 to 2012. Medication use in women of childbearing age (including pregnant women) was identified using pharmaceutical dispensing data for a 10% random sample of the Australian population. Pregnant social security beneficiaries (n = 111 612) were age-matched (1:3) to female social security beneficiaries in the 10% sample. For each medication, the risk it was dispensed during pregnancy relative to being dispensed during an equivalent time period among matched controls was computed. Medications were mapped to Australian pregnancy risk categories. RESULTS: Of the 181 included medications, 35 were statistically significantly more commonly dispensed to pregnant women than control women. Of these, 23 are categorised as posing no increased risk to the foetus. Among medications suspected of causing harm or having insufficient safety data, the strongest associations were observed for hydralazine, ondansetron, dalteparin sodium and ranitidine. Use was less likely during pregnancy than control periods for 127 medications, with the strongest associations observed for hormonal contraceptives and progestogens. CONCLUSIONS: Most medications found to be used disproportionately more by pregnant women are indicated for pregnancy-related problems. A large number of medications were used disproportionately less among pregnant women, where avoidance of some of these medications may pose a greater risk of harm. For many other medications avoided during pregnancy, current data are insufficient to inform this risk-benefit assessment.

Validity of algorithms for identifying five chronic conditions in MedicineInsight, an Australian national general practice database.

BACKGROUND: MedicineInsight is a database containing de-identified electronic health records (EHRs) from over 700 Australian general practices. It is one of the largest and most widely used primary health care EHR databases in Australia. This study examined the validity of algorithms that use information from various fields in the MedicineInsight data to indicate whether patients have specific health conditions. This study examined the validity of MedicineInsight algorithms for five common chronic conditions: anxiety, asthma, depression, osteoporosis and type 2 diabetes. METHODS: Patients' disease status according to MedicineInsight algorithms was benchmarked against the recording of diagnoses in the original EHRs. Fifty general practices contributing data to MedicineInsight met the eligibility criteria regarding patient load and location. Five were randomly selected and four agreed to participate. Within each practice, 250 patients aged ≥ 40 years were randomly selected from the MedicineInsight database. Trained staff reviewed the original EHR for as many of the selected patients as possible within the time available for data collection in each practice. RESULTS: A total of 475 patients were included in the analysis. All the evaluated MedicineInsight algorithms had excellent specificity, positive predictive value, and negative predictive value (above 0.9) when benchmarked against the recording of diagnoses in the original EHR. The asthma and osteoporosis algorithms also had excellent sensitivity, while the algorithms for anxiety, depression and type 2 diabetes yielded sensitivities of 0.85, 0.89 and 0.89 respectively. CONCLUSIONS: The MedicineInsight algorithms for asthma and osteoporosis have excellent accuracy and the algorithms for anxiety, depression and type 2 diabetes have good accuracy. This study provides support for the use of these algorithms when using MedicineInsight data for primary health care quality improvement activities, research and health system policymaking and planning.

Use of smoking cessation pharmacotherapies during pregnancy is not associated with increased risk of adverse pregnancy outcomes: a population-based cohort study.

BACKGROUND: Varenicline, bupropion and nicotine replacement therapy (NRT) are three effective pharmacotherapies for smoking cessation, but data about their safety in pregnancy are limited. We assessed the risk of adverse perinatal outcomes and major congenital anomalies associated with the use of these therapies in pregnancy in Australia. METHODS: Perinatal data for 1,017,731 deliveries (2004 to 2012) in New South Wales and Western Australia were linked to pharmaceutical dispensing, hospital admission and death records. We identified 97,875 women who smoked during pregnancy; of those, 233, 330 and 1057 were exposed to bupropion, NRT and varenicline in pregnancy, respectively. Propensity scores were used to match exposed women to those who were unexposed to any smoking therapy (1:10 ratio). Propensity scores and gestational age at exposure were used to match varenicline-exposed to NRT-exposed women (1:1 ratio). Time-dependent Cox proportional hazards models estimated hazard ratios (HR) with 95% confidence intervals (95% CI) for any adverse perinatal event (a composite of 10 unfavourable maternal and neonatal outcomes) and any major congenital anomaly. RESULTS: The risk of any adverse perinatal event was not significantly different between bupropion-exposed and unexposed women (39.2% versus 39.3%, HR 0.93, 95% CI 0.73-1.19) and between NRT-exposed and unexposed women (44.8% vs 46.3%, HR 1.02, 95% CI 0.84-1.23), but it was significantly lower in women exposed to varenicline (36.9% vs 40.1%, HR 0.86, 95% CI 0.77-0.97). Varenicline-exposed infants were less likely than unexposed infants to be born premature (6.5% vs 8.9%, HR 0.72, 95% CI 0.56-0.92), be small for gestational age (11.4% vs 15.4%, HR 0.68, 95% CI 0.56-0.83) and have severe neonatal complications (6.6% vs 8.2%, HR 0.74, 95% CI 0.57-0.96). Among infants exposed to varenicline in the first trimester, 2.9% had a major congenital anomaly (3.5% in unexposed infants, HR 0.91, 95% CI 0.72-1.15). Varenicline-exposed women were less likely than NRT-exposed women to have an adverse perinatal event (38.7% vs 51.4%, HR 0.58, 95% CI 0.33-1.05). CONCLUSIONS: Pregnancy exposure to smoking cessation pharmacotherapies does not appear to be associated with an increased risk of adverse birth outcomes. Lower risk of adverse birth outcomes in varenicline-exposed pregnancies is inconsistent with recommendations that NRT be used in preference to varenicline.

Prevalence trends and individual patterns of antiepileptic drug use in pregnancy 2006-2016: A study in the five Nordic countries, United States, and Australia.

PURPOSE: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching. METHODS: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester. RESULTS: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%). CONCLUSIONS: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED.

Utilisation of teratogenic medicines before and during pregnancy in Australian women.

BACKGROUND: Given the potential hazards of teratogenic medicines, to a fetus exposed in utero, monitoring their use around pregnancy is imperative. AIM: To measure utilisation of teratogenic medicines (Therapeutic Goods Administration's category D or X) in women who gave birth in New South Wales, Australia, during pregnancy and the 24 months prior. MATERIALS AND METHODS: We used linked population-based datasets including dispensing and perinatal data for all deliveries in NSW between 2005 and 2012. We included pregnancies among concessional beneficiaries only, with complete ascertainment of dispensing claims. Pre-pregnancy and during-pregnancy periods were based on birth dates and gestational age. We determined prevalence of exposure using percent of pregnancies in which women had at least one dispensed teratogenic medicine in three-month time periods. RESULTS: The study included 191 588 pregnancies (145 419 women). Prevalence of exposure to D/X medicines anytime during pregnancy was 2.0% (<20 pregnancies category X), decreasing from pre-pregnancy (3.8-6.0%) to first trimester (1.5%), further decreasing in second and third trimesters (0.8% and 0.6% respectively). We observed large reductions in antibiotic prevalence but only modest reductions for psychotropics and antilipidemic agents (all category D). Our results suggest higher use of potentially teratogenic medicines (category D) than those strictly contraindicated for use (category X), during pregnancy. Overall, use was higher in the first trimester than the rest of pregnancy. The high prevalence of potentially contraindicated psychotropics in all three trimesters may suggest a higher benefit-to-risk ratio and warrants future research focusing on the reasons for their prescribing to pregnant women.

Identifying patients using antidepressants for the treatment of depression: A predictive algorithm for use in pharmaceutical and medical claims data.

PURPOSE: Records of antidepressant dispensings are often used as a surrogate measure of depression. However, as antidepressants are frequently prescribed for indications other than depression, this is likely to result in misclassification. This study aimed to develop a predictive algorithm that identifies patients using antidepressants for the treatment of depression. METHODS: Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule (MBS) claims data were linked to follow-up questionnaires (completed in 2012-2013) for participants of the 45 and Up Study-a cohort study of residents of New South Wales, Australia, aged 45 years and older. The sample composed participants who were dispensed an antidepressant in the 30 days prior to questionnaire completion (n = 3162). An algorithm based on patient characteristics, pharmaceutical dispensings, and claims for mental health services was built using group-lasso interaction network (glinternet), with self-reported receipt of treatment for depression as the outcome. The predictive performance of the algorithm was assessed via bootstrap resampling. RESULTS: The algorithm composes 15 main effects and 11 interactions, with type of antidepressant dispensed and claims for mental health services the strongest predictors. The ability of the algorithm to discriminate between antidepressant users with and without depression was 0.73. At a predicted probability cut-off of 0.6, specificity was 93.8% and sensitivity was 23.6%. CONCLUSIONS: Using this algorithm with a high probability cut-off yields high specificity and facilitates the exclusion of individuals using antidepressants for indications other than depression, thereby mitigating the risk of confounding by indication when evaluating the outcomes of antidepressant use.

Trajectories of antipsychotic use before and during pregnancy and associated maternal and birth characteristics.

OBJECTIVE: To identify distinct trajectories of antipsychotic use prior to and during pregnancy and describe the associated maternal and birth characteristics. METHODS: We conducted a population-based cohort study of births (2005-2012) using linked administrative data in New South Wales, Australia. We used group-based trajectory modelling to classify trajectories of antipsychotic use in the 450 days prior to pregnancy and during pregnancy. We characterised women with different trajectories according to maternal sociodemographic characteristics, mental health diagnoses and hospitalisations, use of psychotropic medicines and birth outcomes. RESULTS: Of 137,993 women who gave birth, 2741 (2.0%) were exposed to antipsychotics prior to or during pregnancy. We identified six trajectories of antipsychotic use: two involved short-term use of low daily doses prior to pregnancy (51.1%), while three involved long-term use of low (20.9%), moderate (11.0%) and high (2.0%) daily doses throughout pregnancy. One trajectory (15.0%) involved increasing use during pregnancy. Women with long-term use were more likely to have a schizophrenia or bipolar disorder diagnosis, to have used multiple psychotropics and to have a mental health hospitalisation during pregnancy. Overall, women using antipsychotics had elevated rates of adverse birth outcomes compared to unexposed women. Women with the greatest antipsychotic exposure had the highest rates of gestational diabetes and gestational hypertension. CONCLUSION: Women using antipsychotics around pregnancy are heterogeneous, with varying patterns of use and associated birth outcomes, reflecting underlying differences in the indications for treatment and/or severity of illness. This diversity should be considered when developing clinical guidelines and designing safety studies.

Multimorbidity among Aboriginal people in New South Wales contributes significantly to their higher mortality.

OBJECTIVES: To compare the prevalence of multimorbidity and its impact on mortality among Aboriginal and non-Aboriginal Australians who had been hospitalised in New South Wales in the previous 10 years. DESIGN, SETTING AND PARTICIPANTS: Cohort study analysis of linked NSW hospital (Admitted Patient Data Collection) and mortality data for 5 437 018 New South Wales residents with an admission to a NSW hospital between 1 March 2003 and 1 March 2013, and alive at 1 March 2013. MAIN OUTCOME MEASURES: Admissions for 30 morbidities during the 10-year study period were identified. The primary outcome was the presence or absence of multimorbidity during the 10-year lookback period; the secondary outcome was mortality in the 12 months from 1 March 2013 to 1 March 2014. RESULTS: 31.5% of Aboriginal patients had at least one morbidity and 16.1% had two or more, compared with 25.0% and 12.1% of non-Aboriginal patients. After adjusting for age, sex, and socio-economic status, the prevalence of multimorbidity among Aboriginal people was 2.59 times that for non-Aboriginal people (95% CI, 2.55-2.62). The prevalence of multimorbidity was higher among Aboriginal people in all age groups, in younger age groups because of the higher prevalence of mental morbidities, and from age 60 because of physical morbidities. The age-, sex- and socio-economic status-adjusted hazard of one-year mortality (Aboriginal v non-Aboriginal Australians) was 2.43 (95% CI, 2.24-2.62), and 1.51 (95% CI, 1.39-1.63) after also adjusting for morbidity count. CONCLUSIONS: The prevalence of multimorbidity was higher among Aboriginal than non-Aboriginal patients, and this difference accounted for much of the difference in mortality between the two groups. Evidence-based interventions for reducing multimorbidity among Aboriginal and Torres Strait Islander Australians must be a priority.