Search

Summary: 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. [ABSTRACT FROM AUTHOR]

Background/Obectives: Oral retinoids are teratogenic, and pregnancy avoidance is an important part of retinoid prescribing. Australia does not have a standardised pregnancy prevention programme for women using oral retinoids, and the contraception strategies for women who use oral retinoids are not well understood. The objectives were to determine trends in the use of prescription retinoids among Australian reproductive‐aged women and whether women dispensed oral retinoids used contraception concomitantly. Methods: This was a population‐based study using Australian Pharmaceutical Benefits (PBS) dispensing claims for a random 10% sample of 15‐44‐year‐old Australian women, 2013 ‐ 2021. We described rates and annual trends in dispensing claims for PBS‐listed retinoids and contraceptives. We also estimated concomitant oral retinoid and contraceptive use on the day of each retinoid dispensing and determined if there was a period of contraceptive treatment that overlapped. Estimates were then extrapolated to the national level. Results: There were 1,545,800 retinoid dispensings to reproductive‐aged women; 57.1% were oral retinoids. The rate of retinoid dispensing to reproductive‐aged women increased annually, from 28 dispensings per 1000 population in 2013 to 41 per 1000 in 2021. The rate of oral retinoid dispensing doubled over the study period, from 14 dispensings per 1000 population in 2013 to 28 per 1000 in 2021, while topical retinoid dispensing did not change. Only 25% of oral retinoid dispensings had evidence of concomitant contraceptive use in 2021. Conclusions: Rates of oral retinoid dispensing have doubled among reproductive‐aged women over the past decade. A large percentage of oral retinoid use does not appear to have concomitant contraception use, posing a risk of teratogenic effects in pregnancies. [ABSTRACT FROM AUTHOR]

Objective: Research points to disparities in disease burden and access to medical care in epilepsy. We studied the association between socioeconomic status (SES) and antiseizure medication (ASM) use in pregnancies with maternal epilepsy. Methods: We conducted a cross‐sectional study consisting of 21 130 pregnancies with maternal epilepsy identified from Nordic registers during 2006–2017. SES indicators included cohabitation status, migrant background, educational attainment, and household income. Main outcomes were the proportion and patterns of ASM use from 90 days before pregnancy to birth. We applied multiple imputation to handle SES variables with 2%–4% missingness. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) using modified Poisson regression with the highest SES category as reference. Results: Mothers with the highest education and the highest income quintile used ASMs least frequently (56% and 53%, respectively). We observed increased risks of ASM discontinuation prior to or during the first trimester for low SES. The risk estimates varied depending on the SES indicator from aRR = 1.27 for low income (95% CI: 1.03–1.57) to aRR = 1.66 for low education (95% CI: 1.30–2.13). Migrant background was associated with ASM initiation after the first trimester (aRR 2.17; 95% CI 1.88–2.52). Low education was associated with the use of valproate during pregnancy in monotherapy (aRR 1.70; 95% CI 1.29–2.24) and in polytherapy (aRR 2.65; 95% CI 1.66–4.21). Low education was also associated with a 37% to 39% increased risk of switching from one ASM to another depending on the ASM used. For the other SES indicators, aRRs of switching varied from 1.16 (foreign origin; 95% CI 1.08–1.26) to 1.26 (not married or cohabiting; 95% CI 1.17–1.36). Significance: Low SES was associated with riskier patterns of ASM use: discontinuation, late initiation, and switching during pregnancy. These findings may reflect unplanned pregnancies, disparities in access to preconception counseling, and suboptimal care. [ABSTRACT FROM AUTHOR]

Background: The Medicines Intelligence (MedIntel) Data Platform is an anonymised linked data resource designed to generate real‐world evidence on prescribed medicine use, effectiveness, safety, costs and cost‐effectiveness in Australia. Results: The platform comprises Medicare‐eligible people who are ≥18 years and residing in New South Wales (NSW), Australia, any time during 2005–2020, with linked administrative data on dispensed prescription medicines (Pharmaceutical Benefits Scheme), health service use (Medicare Benefits Schedule), emergency department visits (NSW Emergency Department Data Collection), hospitalisations (NSW Admitted Patient Data Collection) plus death (National Death Index) and cancer registrations (NSW Cancer Registry). Data are currently available to 2022, with approval to update the cohort and data collections annually. The platform includes 7.4 million unique people across all years, covering 36.9% of the Australian adult population; the overall population increased from 4.8 M in 2005 to 6.0 M in 2020. As of 1 January 2019 (the last pre‐pandemic year), the cohort had a mean age of 48.7 years (51.1% female), with most people (4.4 M, 74.7%) residing in a major city. In 2019, 4.4 M people (73.3%) were dispensed a medicine, 1.2 M (20.5%) were hospitalised, 5.3 M (89.4%) had a GP or specialist appointment, and 54 003 people died. Anti‐infectives were the most prevalent medicines dispensed to the cohort in 2019 (43.1%), followed by nervous system (32.2%) and cardiovascular system medicines (30.2%). Conclusion: The MedIntel Data Platform creates opportunities for national and international research collaborations and enables us to address contemporary clinically‐ and policy‐relevant research questions about quality use of medicines and health outcomes in Australia and globally. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to characterize the use of higher doses of folic acid (≥1 mg daily) in relation to pregnancy in Denmark, Norway, and Sweden in women with epilepsy treated with antiseizure medication (ASM). Methods: In this observational study, we used data from national medical birth, patient, and prescription registers in Denmark, Norway, and Sweden to retrospectively identify pregnancies in women with epilepsy treated with ASM from 2006 to 2017. The proportion of higher dose folic acid supplementation in pregnancies among women receiving ASM for epilepsy was calculated according to country of origin, time period, and type of ASM. Logistic regression with restricted cubic splines was used to model country‐specific time trends. Results: Among a total of 2 748 882 pregnancies, we identified 8695 (.3%) pregnancies after restricting the population to women with ASM‐treated epilepsy. A prescription for higher dose folic acid was filled in 4719 (54.3%) of these pregnancies. The proportion supplemented with higher dose folic acid was highest in Sweden (74.3%) and lower in Norway (41.4%) and Denmark (34.3%). Furthermore, we observed a decreasing trend of higher dose folic acid use in Denmark and Norway from year 2012 to 2017. Among those who used higher dose folic acid, 42% did not start preconception supplementation with higher dose folic acid. Significance: Supplementation with higher dose folic acid occurred in approximately half of pregnancies in women with ASM‐treated epilepsy, with many not starting supplementation until after becoming pregnant. Considerable variability was observed in the use of higher dose folic acid across the countries, despite similar population characteristics and health care systems. Future guidelines should be simplified with clear recommendations developed in a collaborative manner by relevant specialists including neurologists, obstetricians, pediatricians, and public health specialists to enhance real‐world applicability. [ABSTRACT FROM AUTHOR]

Aims: There are increasing concerns about harms related to suboptimal antipsychotic use. Here we describe recent population‐based trends in antipsychotic use and harms in Australia and identify population groups exhibiting patterns of use likely to contribute to these harms. Methods: Using population‐based data from the Australian Pharmaceutical Benefits Scheme (2015‐2020), poisoning calls to the New South Wales (NSW) Poisons Information Centre (2015‐2020) and poisoning deaths in all coronial records (2005‐2018) in Australia, we measured trends in the prevalence of antipsychotic use and related deaths and poisonings. We applied latent class analyses to identify patterns of antipsychotic use that may contribute to harms. Results: Quetiapine and olanzapine had the highest prevalence of use between 2015 and 2020. Noteworthy trends included increases of 9.1% and 30.8% in quetiapine use and poisonings, while olanzapine use decreased by 4.5% but poisonings increased by 32.7%. Quetiapine and olanzapine poisonings and related deaths had the highest rates of co‐ingestion of opioids, benzodiazepines and pregabalin compared to other antipsychotics. We identified six distinct population groups using antipsychotics: (i) ongoing high‐dose use with sedatives (8%), (ii) ongoing use (42%), (iii) ongoing use with analgesics and sedatives (11%), (iv) long‐term low‐dose use (9%), (v) sporadic use (20%) and (vi) sporadic use with analgesics (10%). Conclusion: Ongoing potentially suboptimal antipsychotic use and associated harms highlight the need to monitor such patterns of use, for example through prescription monitoring systems. [ABSTRACT FROM AUTHOR]

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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 at <1–5%, and clonazepam at <1–2%. 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. [ABSTRACT FROM AUTHOR]

Introduction: 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. Material and methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Medicine prescribing for children is impacted by a lack of paediatric‐specific dosing, efficacy and safety data for many medicines. Objectives: To estimate the prevalence of medicine use among children and the rate of 'off‐label' prescribing according to age at dispensing. Methods: 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). Results: 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 children <1 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 children <1 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%). Conclusions: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: 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. Methods: 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. Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Aims: We investigated anticholinergic medicines use among older adults initiating dementia medicines. Methods: We used Pharmaceutical Benefits Scheme dispensing claims to identify patients who initiated donepezil, rivastigmine, galantamine or memantine between 1 January 2013 and 30 June 2017 (after a period of ≥180 days with no dispensing of these medicines) and remained on therapy for ≥180 days (n = 4393), and dispensed anticholinergic medicines in the 180 days before and after initiating dementia medicines. We further examined anticholinergic medicines prescribed by a prescriber other than the one initiating dementia medicines. Results: One‐third of the study cohort (1439/4393) was exposed to anticholinergic medicines up to 180 days before or after initiating dementia medicines. Among patients exposed to anticholinergic medicines, 46% (659/1439) had the same medicine dispensed before and after initiating dementia medicines. The proportion of patients dispensed anticholinergic medicines increased by 2.5% (95% confidence interval [CI]: 1.3–3.7) after initiating dementia medicines. Antipsychotics use increased by 10.1% (95% CI: 7.6–12.7) after initiating dementia medicines; driven by increased risperidone use (7.3%, 95% CI: 5.3–9.3). Nearly half of patients dispensed anticholinergic medicines in the 180 days after (537/1133), were prescribed anticholinergic medicines by a prescriber other than the one initiating dementia medicines. Conclusion: Use of anticholinergic medicines is common among patients initiating dementia medicines and this occurs against a backdrop of widespread campaigns to reduce irrational medicine combinations in this vulnerable population. Decisions about deprescribing medicines with questionable benefit among patients with dementia may be complicated by conflicting recommendations in prescribing guidelines. [ABSTRACT FROM AUTHOR]

Purpose Countries worldwide are developing a variety of strategies to combat the opioid epidemic, such as restricting access to high‐strength opioid formulations. We aimed to examine the dispensing patterns of strong opioids by dose units (DUs), age, and sex. Methods: We used Australian population‐level dispensing data from January 2003 to December 2015 and categorised strong opioids by DU: very low, low, moderate, and high, corresponding to total daily doses of less than or equal to 25, 26 to 50, 51 to 100, and greater than 100 morphine milligramme equivalents, respectively. We measured trends in strong opioid use as dispensings/1000 population/year and stratified dispensing in 2015 by patient age and sex. Results: From 2003 to 2015, strong opioid dispensing of very low, low, moderate, and high DU increased 6.7‐, 6.2‐, 2.2‐, and 1.8‐fold, respectively. The increase in very low and low DU dispensing was driven primarily by oxycodone (5, 10, and 15 mg tablets and capsules) and buprenorphine transdermal patches. In 2015, the number of dispensings/1000 population for very low, low, moderate, and high DU were 180.3, 77.0, 52.7, and 34.8, respectively. Females aged greater than or equal to 85 years had the highest opioid use, ranging from 157.1 dispensings/1000 population for high DU to 2104.5 dispensings/1000 population for very low DU. In contrast, the high DU dispensings in males aged 25 to 64 years exceeded their female counterparts by approximately 1.3‐fold. Conclusion: Relative to moderate and high DU strong opioids, dispensing of very low and low DU strong opioids increased dramatically during the study period in Australia. Future studies investigating opioids use and harms in elderly females and males between 25 to 64 years are warranted. [ABSTRACT FROM AUTHOR]

Purpose Increased expression of Vacuolar‐type H+ ATPases (V‐ATPases), in the plasma membrane of cancer cells has been suggested to contribute to the development of aggressive cancer phenotypes by promoting acidic tumor microenvironments. Accumulating data suggest that proton pump inhibitors (PPIs) may elicit a chemopreventive effect via V‐ATPase inhibition in some cancers, but evidence is still limited. Therefore, we aimed to explore a potential preventive role of PPIs in this study. Methods: In this population‐based case‐control study, we identified incident cases of breast cancer (n = 1739), prostate cancer (n = 1897), and malignant melanoma (n = 385) in Iceland between 2005 and 2014 from the Icelandic Cancer Registry. We assessed varying levels of PPI use through record linkages to the Icelandic Medicines Registry. For each case, we selected up to 10 age‐matched, sex‐matched, and calendar‐matched population controls using risk‐set sampling. Using conditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) controlling for NSAID use. Results: Adjusted ORs associated with ever use of PPIs were 1.03 (95% CI: 0.92‐1.16) for breast cancer, 1.12 (95% CI: 1.00‐1.25) for prostate cancer, and 0.84 (95% CI: 0.69‐1.12) for malignant melanoma. Analyses of high use of PPIs (≥1000 DDDs) yielded ORs of 0.97 (95% CI: 0.78‐1.19), 1.20 (0.99‐1.47), and 0.59 (0.40‐1.13) for breast cancer, prostate cancer, and malignant melanoma, respectively. Analyses of cumulative exposure to PPIs did not support a dose‐response relationship for any of the three cancer types. Conclusions: Our findings do not support a chemopreventive effect of PPI use on breast cancer, prostate cancer, or malignant melanoma. [ABSTRACT FROM AUTHOR]

Study Objective: Evidence on the cardiotoxicity of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), particularly diclofenac and the newer selective cyclooxygenase (COX)‐2 inhibitors, has accumulated over the last decade. Our objective was to examine whether the use of NSAIDs in the Nordic countries changed with the emerging evidence, regulatory statements, and clinical guidelines advocating caution for the use of specific NSAIDs. Design: Drug utilization study. Data Sources: Nationwide wholesale statistics and prescription registries in Denmark, Finland, Iceland, Norway, and Sweden (2000–2016). Measurements and Main Results: Our main outcome measures were yearly total sales, expressed as number of sold defined daily doses (DDDs)/1000 inhabitants/day, and yearly prevalence of prescription use, expressed as number of prescription users per 1000 inhabitants. The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults. Total sales of NSAIDs increased in all countries and were highest in Iceland, with 74.3 DDDs/1000 inhabitants/day sold in 2016, followed by Finland (73.9), Sweden (54.4), Norway (43.8), and Denmark (31.8). Diclofenac use declined after 2008 in all countries but remained the most widely prescribed NSAID in Norway, with 63 prescription users/1000 inhabitants in 2016. Diclofenac sales also remained high in Iceland (12.7 DDD/1000 inhabitants/day), Norway (8.1), and Sweden (7.8). Since its introduction in 2003, the use of etoricoxib, a newer selective COX‐2 inhibitor, increased in all countries except Denmark, with highest sales in Finland (6.7 DDD/1000 inhabitants/day in 2016). Conclusion: Sales and prescription patterns of NSAIDs in the Nordic countries has changed along with the accumulating evidence for the cardiovascular risks of specific NSAIDs. However, given existing evidence on the cardiovascular risks associated with the use of diclofenac and etoricoxib, the persistent high use of diclofenac in Iceland, Norway, and Sweden, the persistent over‐the‐counter availability of diclofenac in Norway and Sweden, and the increasing use of etoricoxib in most of the Nordic countries pose a cardiovascular health concern. [ABSTRACT FROM AUTHOR]

Background: Population data on obstetric interventions is often limited to cesarean delivery. We aimed to provide a more comprehensive overview of trends in use of several common obstetric interventions over the past 2 decades. Methods: The study was based on nationwide data from the Icelandic Medical Birth Register. Incidence of labor induction, epidural analgesia, cesarean, and instrumental delivery was calculated for all births in 1995‐2014. Change over time was expressed as relative risk (RR), using Poisson regression with 95% confidence intervals (CI) adjusted for several maternal and pregnancy‐related characteristics. Analyses were stratified by women's parity and diagnosis of diabetes or hypertensive disorder. Results: During the study period, there were 81 389 intended vaginal births and 5544 elective cesarean deliveries. Among both primiparous and multiparous women, we observed a marked increase across time for labor induction (RR 1.78 [CI 1.67‐1.91] and RR 1.83 [CI 1.73‐1.93], respectively) and epidural analgesia (RR 1.40 [CI 1.36‐1.45] and RR 1.74 [CI 1.66‐1.83], respectively). A similar trend of smaller magnitude was observed among women with hypertensive disorders but no time trend was observed among women with diabetes. Incidence of cesarean and instrumental delivery remained stable across time. Discussion: The use of labor induction and epidural analgesia increased considerably over time, while the cesarean delivery rate remained low and stable. Increases in labor induction and epidural analgesia were most pronounced for women without a diagnosis of diabetes or hypertensive disorder and were not explained by maternal characteristics such as advanced age. [ABSTRACT FROM AUTHOR]

Use of stimulants to treat attention-deficit/hyperactivity disorder ( ADHD) has increased over the past two decades and varies substantially between countries. The objective of this multinational population-based study was to examine utilization of ADHD drugs (stimulants and atomoxetine) including comedication with other psychotropic drugs in the entire child population in the five Nordic countries. We included longitudinal data on dispensed ADHD drugs from five Nordic prescription registers during 2008-2012, which in 2012 comprised 48,296 individuals among 5.42 million inhabitants aged 0-17 years. Prevalence of filling ≥1 prescriptions of ADHD drugs among children aged 6-17 years increased during 2008-2012 from 5.9 to 11.2 and 19.4 to 31.0 per 1000 girls and boys, respectively. Prevalence by country showed that Iceland, Finland and Sweden had a steady increase during the study period, while in Norway the prevalence was quite stable and in Denmark it levelled off from 2010. Use in preschoolers (aged 0-5 years) was rare. Iceland had much higher prevalence and incidence than the other Nordic countries. The incidence of ADHD drug use increased during the study period, from 4.0 to 4.9 and from 1.5 to 2.3 per 1000 boys and girls, respectively. The increasing number of new users levelled off somewhat after 2010. Comedication with other psychotropic drugs was more common among girls (33.9%) than boys (27.0%) and was mainly melatonin, followed by antidepressants and antipsychotics. Overall prevalence of ADHD drug use increased among Nordic girls and boys aged 6-17 years, whereas the incidence increased slightly during 2008-2010 but levelled off through 2012. The substantial differences in ADHD drug use across the Nordic countries and high degree of comedication with other psychotropic drugs underscore the importance of close monitoring of treatment for ADHD among children. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance This study was undertaken to study whether high‐dose folic acid (>1 mg daily) use is associated with an increased risk of cancer in all women who have given birth and in women with epilepsy. High‐dose folic acid supplementation during pregnancy has been linked to increased cancer risk in children born to mothers with epilepsy.We identified women with their first pregnancy in Denmark (1997–2017), Norway (2005–2017), and Sweden (2006–2017) using medical birth registers, linking individual data across nationwide health registers and statistical agencies. Exposure was defined as filled prescriptions for high‐dose folic acid, considered time‐varyingly. The primary outcome was the first malignant cancer diagnosis. Hazard ratios (HRs) of cancer after high‐dose folic acid exposure were estimated using Cox proportional hazard models with 95% confidence intervals (CIs), adjusted for confounders including antiseizure medication (ASM) use, and stratified by maternal epilepsy diagnosis. A 6‐month time lag was applied, as cancer is unlikely to develop immediately.With up to 21 years of follow‐up, we identified 1 465 785 women who gave birth, including 64 485 (4.4%) exposed to high‐dose folic acid. In the exposed group, 755 cancer cases were observed (208 per 100 000 person‐years, 95% CI = 193.8–223.5), compared with 18 702 cases in the unexposed group (164 per 100 000 person‐years, 95% CI = 161.5–166.2), yielding a 20% increased cancer risk overall (adjusted HR = 1.2, 95% CI = 1.1–1.2). This risk was attenuated after the 6‐month lag analysis (adjusted HR = 1.1, 95% CI = 1.04–1.2). The risk for non‐Hodgkin lymphoma was increased in all analyses (n = 28, adjusted HR = 2.0, 95% CI = 1.3–2.9). The association between high‐dose folic acid use and overall cancer risk was similar in those with epilepsy regardless of ASM use (adjusted HR = 1.3, 95% CI = 1.0–1.8).High‐dose folic acid use was associated with increased overall cancer risk in women who have given birth, with a consistent association with non‐Hodgkin lymphoma, including those with epilepsy, regardless of ASM use. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions There are limited contemporary population‐based studies on the risk factors for hyperemesis gravidarum (HG), a severe type of nausea and vomiting in pregnancy. This study aimed to determine the prevalence and trend of HG over time, identify risk factors for any and multiple HG health service visits during pregnancy, and investigate HG recurrence across pregnancies.This population‐based record linkage cohort study featured births in New South Wales, Australia from 2010 to 2019. Hospital and emergency data collections were used to identify health service visits for HG using relevant diagnosis codes and were linked to the corresponding pregnancy on the birth data set. Outcomes included any HG and multiple HG visits during pregnancy, and HG recurrence across pregnancies. Annual HG prevalence was calculated, and negative binomial regression was used to examine standardized prevalence trends. Risk factors for any HG and multiple HG visits within a pregnancy were examined using Robust Poisson models with generalized estimating equations and Prentice–Williams–Peterson Gap Time models, respectively. Rates and risk of recurrence were calculated for women with a second and third pregnancy.Of the 955 107 pregnancies, 21 702 (2.3%) were classified as HG. There was an average annual increase of 6.8% (95% CI 5.3–8.3) in HG prevalence. Younger maternal age, multiple pregnancies, and selected preexisting conditions were associated with an increased risk of HG, with the strongest factor being HG in any previous pregnancy (risk ratio 8.92, 99% CI 8.43–9.44). Hyperemesis gravidarum recurrence at the second (28.9%) and third (54.7%) pregnancies was high.Hyperemesis gravidarum history is the strongest risk factor for HG, which has implications for counseling and care that women receive around pregnancy. [ABSTRACT FROM AUTHOR]

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., (© 2024 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Background: Population data on obstetric interventions is often limited to cesarean delivery. We aimed to provide a more comprehensive overview of trends in use of several common obstetric interventions over the past 2 decades., Methods: The study was based on nationwide data from the Icelandic Medical Birth Register. Incidence of labor induction, epidural analgesia, cesarean, and instrumental delivery was calculated for all births in 1995-2014. Change over time was expressed as relative risk (RR), using Poisson regression with 95% confidence intervals (CI) adjusted for several maternal and pregnancy-related characteristics. Analyses were stratified by women's parity and diagnosis of diabetes or hypertensive disorder., Results: During the study period, there were 81 389 intended vaginal births and 5544 elective cesarean deliveries. Among both primiparous and multiparous women, we observed a marked increase across time for labor induction (RR 1.78 [CI 1.67-1.91] and RR 1.83 [CI 1.73-1.93], respectively) and epidural analgesia (RR 1.40 [CI 1.36-1.45] and RR 1.74 [CI 1.66-1.83], respectively). A similar trend of smaller magnitude was observed among women with hypertensive disorders but no time trend was observed among women with diabetes. Incidence of cesarean and instrumental delivery remained stable across time., Discussion: The use of labor induction and epidural analgesia increased considerably over time, while the cesarean delivery rate remained low and stable. Increases in labor induction and epidural analgesia were most pronounced for women without a diagnosis of diabetes or hypertensive disorder and were not explained by maternal characteristics such as advanced age., (© 2018 Wiley Periodicals, Inc.)