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Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ-sedatives, BZ-hypnotics, and benzodiazepine-related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000-2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55-78% of BZ use in 2020, followed by BZ sedatives at 20-44%, BZ-hypnotics at1-5%, and clonazepam at1-2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups-despite warnings against their use in this population.

Use of labor induction has increased rapidly in most middle- and high-income countries over the past decade. The reasons for the stark rise in labor induction are largely unknown. We aimed to assess the extent to which the rising rate of labor induction is explained by changes in rates of underlying indications over time.The study was based on nationwide data from the Icelandic Medical Birth Register on 85 620 singleton births from 1997 to 2018. The rate of labor induction and indications for induction was calculated for all singleton births in 1997-2018. Change over time was expressed as relative risk (RR), using Poisson regression with 95% confidence intervals (CI) adjusted for maternal characteristics and indications for labor induction.The crude rate of labor induction rose from 12.5% in 1997-2001 to 23.9% in 2014-2018 (crude RR = 1.91, 95% CI 1.81-2.01). While adjusting for maternal characteristics had little impact, adjusting additionally for labor induction indications lowered the RR to 1.43 (95% CI 1.35-1.51). Induction was increasingly indicated from 1997-2001 to 2014-2018 by gestational diabetes (2.4%-16.5%), hypertensive disorders (7.0%-11.1%), prolonged pregnancy (16.2%-23.7%), concerns for maternal wellbeing (3.2%-6.9%) and maternal age (0.5%-1.2%). No indication was registered for 9.2% of inductions in 2014-2018 compared with 16.3% in 1997-2001.Our results show that the increase in labor induction over the study period is largely explained by an increase in various underlying conditions indicating labor induction. However, indications for 9.2% of labor inductions remain unexplained and warrant further investigation.

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.

Background: Depression and anxiety affect 4–14% of Australians every year; symptoms may have been exacerbated during the COVID-19 pandemic. We examined recent patterns of antidepressant use in Australia in the period 2015–2021, which includes the first year of the pandemic. Methods: We used national dispensing claims for people aged ⩾10 years to investigate annual trends in prevalent and new antidepressant use (no antidepressants dispensed in the year prior). We conducted stratified analyses by sex, age group and antidepressant class. We report outcomes from 2015 to 2019 and used time series analysis to quantify changes during the first year of the COVID-19 pandemic (March 2020–February 2021). Results: In 2019, the annual prevalence of antidepressant use was 170.4 per 1000 women and 101.8 per 1000 men, an increase of 7.0% and 9.2% from 2015, respectively. New antidepressant use also increased for both sexes (3.0% for women and 4.9% for men) and across most age groups, particularly among adolescents (aged 10–17 years; 46–57%). During the first year of the COVID-19 pandemic, we observed higher than expected prevalent use (+2.2%, 95% CI = [0.3%, 4.2%]) among females, corresponding to a predicted excess of 45,217 (95% CI = [5,819, 84,614]) females dispensed antidepressants. The largest increases during the first year of the pandemic occurred among female adolescents for both prevalent (+11.7%, 95% CI = [4.1%, 20.5%]) and new antidepressant use (+15.6%, 95% CI = [8.5%, 23.7%]). Conclusion: Antidepressant use continues to increase in Australia overall and especially among young people. We found a differential impact of the COVID-19 pandemic in treated depression and anxiety, greater among females than males, and greater among young females than other age groups, suggesting an increased mental health burden in populations already on a trajectory of increased use of antidepressants prior to the pandemic. Reasons for these differences require further investigation.

Medicine prescribing for children is impacted by a lack of paediatric-specific dosing, efficacy and safety data for many medicines.To estimate the prevalence of medicine use among children and the rate of 'off-label' prescribing according to age at dispensing.We used population-wide primarily outpatient dispensing claims data for 15% of Australian children (0-17 years), 2013-2017 (n = 840,190). We estimated prescribed medicine use and 'off-label' medicine use according to the child's age (1 year, 1-5 years, 6-11 years, 12-17 years) defined as medicines without age-appropriate dose recommendations in regulator-approved product information. Within off-label medicines, we also identified medicines with and without age-specific dose recommendations in a national prescribing guide, the Australian Medicines Handbook Children's Dosing Companion (AMH CDC).The overall dispensing rate was 2.0 dispensings per child per year. The medicines with the highest average yearly prevalence were systemic antibiotics (435.3 per 1000 children), greatest in children 1-5 years (546.9 per 1000). Other common medicine classes were systemic corticosteroids (92.7 per 1000), respiratory medicines (91.2 per 1000), acid-suppressing medicines in children1 year (47.2 per 1000), antidepressants in children 12-17 years (40.3 per 1000) and psychostimulants in children 6-11 years (27.0 per 1000). We identified 12.2% of dispensings as off-label based on age, but 66.3% of these had age-specific dosing recommendations in the AMH CDC. Among children1 year, off-label dispensings were commonly acid-suppressing medicines (35.5%) and topical hydrocortisone (33.1%); in children 6-11 years, off-label prescribing of clonidine (16.0%) and risperidone (13.1%) was common. Off-label dispensings were more likely to be prescribed by a specialist (21.7%) than on-label dispensings (7.5%).Prescribed medicine use is common in children, with off-label dispensings for medicines without paediatric-specific dosing guidelines concentrated in classes such as acid-suppressing medicines and psychotropics. Our findings highlight a need for better evidence to support best-practice prescribing.

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from −90% to +30%, were reported in many countries following early COVID-19 pandemic response measures (‘lockdowns’). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95–0.98, P value

ImportancePsychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps.ObjectiveTo evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes.Design, Setting, and ParticipantsThis cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022.ExposuresOne or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs.Main Outcomes and MeasuresAny major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization.ResultsA total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions.Conclusions and RelevanceIn this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

In May 2019, Australia's Pharmaceutical Benefits Scheme (PBS) tightened the prescribing restrictions for publicly subsidized high and standard strength proton-pump inhibitors (PPIs). We aimed to determine the impacts on PPI use in Australia.Population-based interrupted time series analysis of PBS dispensing claims for a 10% sample of PBS-eligible Australian residents from January 2017 to December 2020 and national prescription and over-the-counter sales to pharmacies from January 2017 to October 2020. We examined trends in monthly PPI dispensings, switches from higher to lower strength formulations, and volume (kg) dispensed and sold.From May 2019, we observed a small, immediate decrease (-7830 [95%CI: -8818 to -6842]) in standard strength PPI dispensings/month, which rebounded to exceed pre-intervention levels by December 2020. High strength dispensings decreased until the end of the study period to less than half their pre-intervention average/month; low strength dispensings/month increased until the end of the study period to more than double their pre-intervention average/month. We observed transient increases in switches to lower strength formulations post-intervention. The kilograms of PPIs sold/month followed a similar pattern to PBS kilograms dispensed/month with the exception of standard strength formulations where PBS dispensings decreased by -74 (95%CI: -93 to -55) but total sales remained unchanged (comprising PBS and private prescriptions, and over-the-counter sales).Tightened prescribing restrictions had an immediate and sustained impact on PPI use in Australia, with decreased high strength use and increased low strength use. Some patients likely switched to private market prescriptions for standard strength PPI, given the observed patterns in total volume sold/dispensed.

BackgroundAntipsychotics are increasingly used among women of childbearing age and during pregnancy.ObjectiveTo determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders.DesignPopulation-based cohort study, including a sibling analysis.SettingNationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016).Participants4 324 086 children were eligible for inclusion to the study cohort.InterventionAntipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use.Main outcome measuresNon-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors.FindingsAmong 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD.DiscussionOur findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics.Clinical implicationsResults regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.

Introduction Previous evidence has been conflicting regarding the effect of coronavirus disease 2019 (COVID‐19) pandemic lockdowns on obstetric intervention and preterm birth rates. The literature to date suggests potentially differential underlying mechanisms based on country economic setting. We aimed to study these outcomes in an Icelandic population where uniform lockdown measures were implemented across the country. Material and methods The study included all singleton births (n = 20 680) during 2016–2020 identified from the population‐based Icelandic Medical Birth Register. We defined two lockdown periods during March–May and October–December in 2020 according to government implemented nationwide lockdown. We compared monthly rates of cesarean section, induction of labor and preterm birth during lockdown with the same time periods in the 4 previous years (2016–2019) using logit binomial regression adjusted for confounders. Results Our results indicated a reduction in the overall cesarean section rate, which was mainly evident for elective cesarean section, both during the first (adjusted odd ratio [aOR] 0.71, 95% CI 0.51–0.99) and second (aOR 0.72, 95% CI 0.52–0.99) lockdown periods, and not for emergency cesarean section. No change during lockdown was observed in induction of labor. Our results also suggested a reduction in the overall preterm birth rate during the first lockdown (aOR 0.69, 95% CI 0.49–0.97) and in the months immediately following the lockdown (June–September) (aOR 0.67, 95% CI 0.49–0.89). The reduction during the first lockdown was mainly evident for medically indicated preterm birth (although not statistically significant) and the reduction during June–September was mainly evident for spontaneous preterm birth. Conclusions This study suggested a reduction in elective cesarean section during COVID‐19 lockdown, possibly reflecting changes in prioritization of non‐urgent health care during lockdown. We also found a reduction in overall preterm birth during the first lockdown and spontaneous preterm birth following the first lockdown, but further research is needed to shed light on the underlying mechanisms for these findings.

Background Proton pump inhibitors (PPIs) are associated with microbiome changes of the gut, which in turn may affect the progression of colorectal cancer (CRC). This study aims to assess the associations between PPI use and all-cause and CRC-specific mortality. Methods We selected all patients registered in the Swedish Prescribed Drug Registry who were diagnosed with CRC between 2006 and 2012 (N = 32,411, 54.9% PPI users) and subsequently followed them through register linkage to the Swedish Causes of Death Registry until December 2013. PPI users were patients with >= 1 post-diagnosis PPI dispensation. Time-dependent Cox-regression models were performed with PPI use as time-varying exposure. Results Overall 4746 (14.0%) patients died, with an aHR of 1.38 (95% CI 1.32-1.44) for all-cause mortality comparing PPI users with PPI nonusers. Higher-magnitude associations were observed among male, cancer stage 0-I, rectal cancer and patients receiving CRC surgery. The PPI-all-cause mortality association was also more pronounced comparing new users to non-users (aHR = 1.47, 95%CI 1.40-1.55) than comparing continuous users to non-users (aHR = 1.32, 95%CI 1.24-1.39). The risk estimates for CRC-specific mortality comparing PPI users to PPI nonusers were similar to those for all-cause mortality. Conclusion PPI use after the CRC diagnosis was associated with increased all-cause and CRC-specific mortality.

ImportanceWomen with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Whether prenatal exposure to high-dose folic acid is associated with increases in the risk of childhood cancer is unknown.ObjectiveTo assess whether high-dose folic acid supplementation in mothers with epilepsy is associated with childhood cancer.Design, Setting, and ParticipantsObservational cohort study conducted with nationwide registers in Denmark, Norway, and Sweden from 1997 to 2017. Analyses were performed during January 10, 2022, to January 31, 2022. Mother-child pairs were identified in medical birth registers and linked with information from patient, prescription, and cancer registers, as well as with sociodemographic information from statistical agencies, and were categorized by maternal diagnosis of epilepsy. The study population consisted of 3 379 171 children after exclusion of 126 711 children because of stillbirth or missing or erroneous values on important covariates.ExposuresMaternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth.Main Outcomes and MeasuresFirst onset of childhood cancer at younger than 20 years. Cox proportional hazards models were used to calculate adjusted hazard ratios with corresponding 95% CIs, adjusted for potential confounders. Cumulative incidence at aged 20 years was used as a measure of absolute risk.ResultsThe median age at the end of follow-up in the study population of 3 379 171 children was 7.3 years (IQR, 3.5-10.9 years). Among the 27 784 children (51.4% male) born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed, producing an adjusted hazard ratio of 2.7 (95% CI, 1.2-6.3), absolute risk if exposed of 1.4% (95% CI, 0.5%-3.6%), and absolute risk if unexposed of 0.6% (95% CI, 0.3%-1.1%). In children of mothers without epilepsy, 46 646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases and an adjusted hazard ratio of 1.1 (95% CI, 0.9-1.4; absolute risk, 0.4% [95% CI, 0.3%-0.5%]). There was no association between children born to mothers with epilepsy who were prenatally exposed to antiseizure medications, but not high-dose folic acid, and an increased risk of cancer (absolute risk, 0.6%; 95% CI, 0.2%-1.3%).Conclusions and RelevancePrenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.

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% (

Proton pump inhibitors (PPIs) are commonly used drugs among cancer patients. Due to conflicting reports on their safety, we aimed to determine whether PPI use is associated with mortality among prostate cancer patients. In this population-based cohort study, we identified incident diagnoses of prostate cancer between 2007 and 2012 (n = 1058). Follow-up was from 12 months after diagnosis until death, emigration or end the of study. Post-diagnosis use was defined as ≥2 filled prescriptions following diagnosis. We used time-dependent Cox proportional hazard regression models to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer-specific and all-cause mortality associated with post-diagnosis use of PPIs. We identified 347 (32.8%) post-diagnosis PPI users and 711 (67.2%) non-users after diagnosis. Of the 347 patients using PPIs after diagnosis, 59 (17.0%) died due to any cause and 22 (6.3%) due to prostate cancer, compared with 144 (20.3%) and 76 (10.7%) among non-users after diagnosis, respectively. Post-diagnosis PPI use was not associated with prostate cancer-specific mortality (HR 0.88; 95% CI: 0.52-1.48) or all-cause mortality (HR 1.02; 95% CI: 0.73-1.43). Contrary to a previous report, this study did not find evidence of an association between post-diagnosis PPI use and mortality among prostate cancer patients.

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.

Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996–2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87–1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70–2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26–2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72–1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83–1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53–1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551–562.

Refereed/Peer-reviewed Australia spends more than $20 billion annually on medicines, delivering significant health benefits for the population. However, inappropriate prescribing and medicine use also result in harm to individuals and populations, and waste of precious health resources. Medication data linked with other routine collections enable evidence generation in pharmacoepidemiology; the science of quantifying the use, effectiveness and safety of medicines in real-world clinical practice. This review details the history of medicines policy and data access in Australia, the strengths of existing data sources, and the infrastructure and governance enabling and impeding evidence generation in the field. Currently, substantial gaps persist with respect to cohesive, contemporary linked data sources supporting quality use of medicines, effectiveness and safety research; exemplified by Australia's limited capacity to contribute to the global effort in real-world studies of vaccine and disease-modifying treatments for COVID-19. We propose a roadmap to bolster the discipline, and population health more broadly, underpinned by a distinct capability governing and streamlining access to linked data assets for accredited researchers. Robust real-world evidence generation requires current data roadblocks to be remedied as a matter of urgency to deliver efficient and equitable health care and improve the health and well-being of all Australians.

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.

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.

Importance: Women with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain. Objective: To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders. Design, Setting, and Participants: The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848). Exposures: Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth. Main Outcomes and Measures: We estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID). Results: A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital. Conclusions and Relevance: In this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevelopmental disorders. publishedVersion

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread “natural experiment” of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic.

Aims Public health responses to reduce SARS-CoV-2 transmission have profoundly affected the epidemiology and management of other infections. We examined the impact of COVID-19 restrictions on antibiotic dispensing in Australia. Methods We used national claims data to investigate antibiotic dispensing trends from November 2015 to October 2020 and whether changes reflected reductions in primary care consultations. We used interrupted time series analysis to quantify changes in monthly antibiotic dispensing and face-to-face and telehealth GP consultations and examined changes by recipient age, pharmacy State and prescriber specialty. Results Over the study period, an estimated 19 921 370 people had 125 495 137 antibiotic dispensings, 71% prescribed by GPs. Following COVID-19 restrictions, we observed a sustained 36% (95% CI: 33-40%) reduction in antibiotic dispensings from April 2020. Antibiotics recommended for managing respiratory tract infections showed large reductions (range 51-69%), whereas those recommended for non-respiratory infections were unchanged. Dispensings prescribed by GPs decreased from 63.5 per 1000 population for April-October 2019 to 37.0 per 1000 for April-October 2020. Total GP consultation rates remained stable, but from April 2020, 31% of consultations were telehealth. Conclusion In a setting with a low COVID-19 incidence, restrictions were associated with a substantial reduction in community dispensings of antibiotics primarily used to treat respiratory infections, coincident with reported reductions in respiratory viral infections. Our findings are informative for post-pandemic antimicrobial stewardship and highlight the potential to reduce inappropriate prescribing by GPs and specialists for respiratory viral infections.

Purpose We quantified changes in dispensing of common medicines proposed for “re-purposing” due to their perceived benefits as therapeutic or preventive treatments for COVID-19 in Australia, a country with relatively low COVID-19 incidence in 2020. Methods We performed an interrupted time series analysis and cross-sectional study using nationwide dispensing claims data (January 2017-November 2020). We focused on six subsidised medicines proposed for re-purposing: hydroxychloroquine, azithromycin, ivermectin, colchicine, corticosteroids, and calcitriol (Vitamin D analogue). We quantified changes in monthly dispensing and initiation trends during COVID-19 (March-November 2020) using autoregressive integrated moving average models (ARIMA) and compared characteristics of initiators in 2020 and 2019. Result In March 2020, we observed a 99% (95%CI 96%-103%) increase in hydroxychloroquine dispensing (of which approximately 30% attributable to new use), and a 201% increase (95%CI 186%-215%) in initiation, with a shift towards prescribing by general practitioners (42% in 2020 vs 25% in 2019) rather than specialists. These increases subsidised following regulatory restrictions on prescribing to relevant specialties. There was also a small but sustained increase in ivermectin dispensing over multiple months, with a 80% (95%CI 42%-119%) increase in initiation in May 2020 following its first identification as potentially disease-modifying in April 2020. Other than increases in March related to stockpiling among existing users, we observed no increases in initiation of calcitriol or colchicine during COVID-19. Dispensing of corticosteroids and azithromycin remained low after March 2020. Conclusions Most increases in dispensing observed early on during COVID-19 were temporary and appear to be related to stockpiling among existing users. However, we observed increases in initiation of hydroxychloroquine and ivermectin and a shift in prescribing patterns, indicating that a small proportion may be COVID-19 related. A quick response by regulators can help limit inappropriate repurposing to lessen the impact on medicine supply and patient harms. Key points In Australia, a country with low incidence of COVID-19 in 2020, most increases in dispensing of medicines proposed for re-purposing for treatment or prevention of COVID-19 were temporary and appeared to be related to stockpiling among existing users We observed a dramatic increase in new users of hydroxychloroquine in March and April 2020, with a shift toward prescribing by general practitioners instead of rheumatologists which subsided after the introduction of restrictions on its prescribing by non-specialists Dispensing of ivermectin also increased during COVID-19, but occurred later and was spread out over several months When such situations arise, a quick response by regulators can help limit inappropriate repurposing to reduce the potential for medicine supply shortages and patient harms

ObjectivesTo assess the trends in medication use indicative of physical and psychological morbidity following the 2010 volcanic eruption in Eyjafjallajökull immediately after and during a 3-year period following the eruption.DesignPopulation-based register study.SettingEyjafjallajökull eruption in Iceland, 2007–2013.ParticipantsAll residents in Iceland who received at least one medication dispensing were identified. Residents of exposed areas were classified into exposure groups (individual-level data) and residents in other parts of Iceland were included as a non-exposed group (aggregated data).Intervention/exposureEyjafjallajökull erupted on 14 April 2010 and continued for 39 days, producing heavy ash fall in South Iceland.Main outcome measuresUsing interrupted time series analysis, we examined annual and quarterly changes in medicine use, measured as number of dispensed defined daily dose (DDD) per 1000 individuals. We calculated the level shift (immediate change) and change in slope from pre-eruption to post-eruption (long-term change) in medication dispensing.ResultsAmong exposed residents, there was a 6% decrease (95% CI -7% to -4%) in the annual number of dispensed DDDs 1-year post-eruption in the overall medication class, including analgesics (−5%, 95% CI -6% to -3%), hypnotics and sedatives (−9%, 95% CI -11% to -7%) and respiratory medications (−7%, 95% CI -9% to -5%; −8%, 95% CI -11% to -4%). Simultaneously, there was a 9% decrease (95% CI -14% to -4%) in the overall medication class among non-exposed residents. Moreover, among exposed residents, we observed change in slope of −4% (95% CI -7% to -1%) in the overall medication class, including for analgesics (−6%, 95% CI -8% to -3%) and other respiratory drugs (−10%, 95% CI -16% to -4%).ConclusionOur findings indicate that the eruption did not lead to increases in medication dispensing among residents of exposed areas, rather decreases for some medicine classes. The results should be interpreted with caution since the content of each eruption differs.

Recent European and US studies reported increased risks of skin cancers associated with hydrochlorothiazide (HCTZ) treatment. Our study aimed to determine the risk of lip cancer and malignant melanoma among Australians prescribed HCTZ. We conducted a case-control study nested within a population of veterans residing in New South Wales in 2004-2015, using Australian Department of Veterans’ Affairs data linked with cancer registrations, hospitalisation and prescription dispensings. Among DVA healthcare card holders 65 years and older, we identified incident cases of squamous cell carcinoma of the lip and of cutaneous melanoma, each matched with up to 20 controls through risk-set sampling. We estimated odds ratios (ORs) associating HCTZ use with each cancer using conditional logistic regression, adjusting for predefined confounders. For lip cancer (45 cases), ever-use of HCTZ yielded an OR of 2.6 (95% CI: 1.4-5.0) and high HCTZ use (≥25 000 mg) an OR of 4.7 (95% CI: 1.6-13.7). For cutaneous melanoma (659 cases), ever-use of HCTZ resulted in an OR of 1.2 (95% CI 1.0-1.5) and high HCTZ use in an OR of 1.2 (95% CI: 0.8-1.8). Our findings align with risk estimates from previous studies and provide further evidence that HCTZ’s photosensitising properties may promote carcinogenesis in sun-exposed tissues.

Background We designed and implemented a new model of care, Enhanced Antenatal Care (EAC), which offers a combined approach to midwifery-led care with six one-to-one visits and four group sessions. Aim To assess EAC in terms of women’s satisfaction with care, autonomy in decision-making, and its effectiveness in lowering childbirth fear. Methods This was a quasi-experimental controlled trial comparing 32 nulliparous women who received EAC (n = 32) and usual antenatal care (n = 60). We compared women’s satisfaction with care and autonomy in decision-making post-intervention using chi-square test. We administered a Fear of Birth Scale pre- and post-intervention and assessed change in fear of birth in each group using the Cohen’s d for effect size. To isolate the effect of EAC, we then restricted this analysis to women who did not attend classes alongside maternal care (n = 13 in EAC and n = 13 in usual care). Findings Women’s satisfaction with care in terms of monitoring their and their baby’s health was similar in both groups. Women receiving EAC were more likely than those in usual care to report having received enough information about the postpartum period (75% vs 30%) and parenting (91% vs 55%). Overall, EAC was more effective than usual care in reducing fear of birth (Cohen’s d = −0.21), especially among women not attending classes alongside antenatal care (Cohen’s d = −0.83). Conclusion This study is the first to report findings on EAC and suggests that this novel model may be beneficial in terms of providing education and support, as well as lowering childbirth fear.

Publisher's version (útgefin grein), Background Proton pump inhibitor (PPI) use is widespread. There have been increasing concerns about overuse of high-dose PPIs for durations longer than clinically necessary. Objective To evaluate the impact of national education initiatives on reducing PPI use in Australia. Design Population-based, controlled interrupted time series analysis of PPI dispensing claims data for Australian adults from July 2012 to June 2018; we used statin dispensing as a control. Interventions A year-long educational initiative led by NPS MedicineWise (previously the National Prescribing Service) from April 2015. Simultaneously, Choosing Wisely released recommendations in April 2015 and May 2016. Both promoted review of prolonged PPI use and encouraged stepping down or ceasing treatment, where appropriate. Measurements We examined monthly changes in PPI (and statin) dispensing (stratified by high, standard and low tablet strength), rates of switching from higher to lower strength PPIs and rates of PPI (and statin) discontinuation. Results We observed 12 040 021 PPI dispensings to 579 594 people. We observed a sustained -1.7% (95% CI: -2.7 to -0.7%) decline in monthly dispensing of standard strength PPIs following the initiatives until the end of the study period. There were no significant changes in high or low strength PPI (or statin) dispensings, switching to lower strength PPIs, or PPI (and statin) treatment discontinuation. Conclusion Our findings suggest that these educational initiatives alone were insufficient in curbing overuse of PPIs on a national level. Concerted efforts with policy levers such as imposing tighter restrictions on subsidised use of PPIs may be more effective. Noting low strength esomeprazole is not publicly subsidised in Australia, availability of these preparations may also facilitate more appropriate practice, This research is supported by the National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Medicines and Ageing (ID: 1060407) and a Cooperative Research Centre Project (CRC-P) Grant from the Australian Government Department of Industry, Innovation and Science (ID: CRC-P-439). Dr Zoega was supported by a Scientia Fellowship from UNSW Sydney. Dr Schaffer was supported by a NHMRC Early Career Fellowship (#1158763).

Background: Proton-pump inhibitors (PPIs) are among the most prescribed medicines worldwide and concern about their long-term use is growing. We used dispensing claims for every person in Australia dispensed publicly subsidized PPIs between 2013 and 2016 to determine the incidence and prevalence of PPI use and to examine the patterns and durations of PPI treatment among individuals continuing treatment beyond the guideline-recommended maximum 12 weeks. Methods: We estimated annual prevalence and incidence per 100 people and duration of treatment for every Australian dispensed publicly subsidized PPIs between 2013 and 2016. We examined patterns of PPI treatment in three patient subgroups using PPIs for more than 12 weeks duration; people receiving maintenance, long-term continuous or long-term intermittent treatment. We calculated the proportion in each subgroup stepping down from higher to lower PPI strengths, stepping up from lower to higher PPI strength and discontinuing treatment. Results: PPIs were dispensed to 4,388,586 people; 60% were women; median age at initiation was 52 years [interquartile range (IQR): 36–65]. Standard and high strength PPIs accounted for 95% of dispensings. Annual incidence and prevalence were 3.9/100 and 12.5/100, respectively, in 2016 and highest among individuals over 65 years (prevalence range: 33–43/100). Most people (67%) stopped treatment after one dispensing; while 25%, 6% and 10% continued on maintenance, long-term continuous and long-term intermittent treatment, respectively. Median duration of treatment in people continuing treatment was 501 days (IQR: 180–not reached) for maintenance treated individuals and ‘not reached’ for long-term treated individuals. We observed 35%, 20% and 47% of people stepping down from higher to lower treatment strengths on maintenance, long-term continuous and long-term intermittent treatment, respectively. Conclusions: Longer-term treatment with higher strength PPIs is common. Targeted regulation of PPI prescribing may improve the uptake of lower strength formulations and reduce both harms and costs associated with long-term PPI treatment.