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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.

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.

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.

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.

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.

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.

Summary Background The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence. Methods We did a retrospective, observational study using population-based databases from 13 countries and one Special Administrative Region (SAR): four in Asia and Australia, two in North America, five in northern Europe, and three in western Europe. We used a common protocol approach to define study populations and parameters similarly across countries and the SAR. Study populations consisted of all individuals aged 3 years or older between Jan 1, 2001, and Dec 31, 2015 (dependent on data availability). We estimated annual prevalence of ADHD medication use with 95% CI during the study period, by country and region and stratified by age and sex. We reported annual absolute and relative percentage changes to describe time trends. Findings 154·5 million individuals were included in the study. ADHD medication use prevalence in 2010 (in children aged 3–18 years) varied between 0·27% and 6·69% in the countries and SAR assessed (0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and 0·70% in western Europe). The prevalence of ADHD medication use among children increased over time in all countries and regions, and the absolute increase per year ranged from 0·02% to 0·26%. Among adults aged 19 years or older, the prevalence of any ADHD medication use in 2010 varied between 0·003% and 1·48% (0·05% in Asia and Australia, 1·42% in North America, 0·47% in northern Europe, and 0·03% in western Europe). The absolute increase in ADHD medication use prevalence per year ranged from 0·0006% to 0·12%. Methylphenidate was the most commonly used ADHD medication in most countries. Interpretation Using a common protocol and data from 13 countries and one SAR, these results show increases over time but large variations in ADHD medication use in multiple regions. The recommendations of evidence-based guidelines need to be followed consistently in clinical practice. Further research is warranted to describe the safety and effectiveness of ADHD medication in the short and long term, and to inform evidence-based guidelines, particularly in adults. Funding None

Objective Previous research reported greater risk of adverse perinatal outcomes associated with first trimester exposure to angiotensin converting enzyme inhibitors (ACEIs) in comparison to unexposed pregnancies among non-hypertensive women. We examined the relationship between first trimester exposure to ACEIs and angiotensin receptor blockers (ARBs), and maternal and perinatal outcomes, whilst controlling for the underlying hypertension. Study design We performed a population-based cohort study among 130,061 pregnancies resulting in birth in NSW, Australia between 2005 and 2012. Birth data were linked to hospital discharge and pharmaceutical dispensing records. After restricting to women with chronic hypertension, 67 and 73 pregnancies exposed to ACEIs and ARBs respectively during the first trimester were compared with 316 pregnancies exposed to methyldopa. Study outcomes Preterm delivery, caesarean section, low birth weight, small for gestational age and Apgar score Results Compared to pregnancies exposed to methyldopa, the adjusted odds ratio (aOR) for ACEI exposure was 0.5 (95% CI: 0.2–1.1) for preterm delivery, 1.6 (0.8–3.1) for caesarean section, 0.6 (0.2–1.3) for LBW and 0.8 (0.4–1.9) for SGA. The corresponding aORs and confidence intervals for ARB exposure were 0.7 (0.3–1.5), 1.2 (0.6–2.6), 1.3 (0.7–2.6), and 1.2 (0.6–2.4). Conclusion No association between early pregnancy exposure to ACEIs and ARBs and perinatal outcomes was observed, however, the possibility of an association cannot be ruled out due to limited power. Nonetheless, this study suggests that the magnitude of risk is smaller than that reported previously.

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.

Importance: Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety.Objective: To examine the risk of congenital malformations associated with intrauterine exposure to stimulants.Design, Setting, and Participants: Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017.Exposures: Methylphenidate and amphetamines dispensed during the first trimester.Main Outcomes and Measures: Major congenital malformations and subgroup of cardiac malformations.Results: In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64).Conclusions and Relevance: These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.

The objective of this study was to assess international trends in antipsychotic use, using a standardised methodology. A repeated cross-sectional design was applied to data extracts from the years 2005 to 2014 from 16 countries worldwide. During the study period, the overall prevalence of antipsychotic use increased in 10 of the 16 studied countries. In 2014, the overall prevalence of antipsychotic use was highest in Taiwan (78.2/1000 persons), and lowest in Colombia (3.2/1000). In children and adolescents (0-19 years), antipsychotic use ranged from 0.5/1000 (Lithuania) to 30.8/1000 (Taiwan). In adults (20-64 years), the range was 2.8/1000 (Colombia) to 78.9/1000 (publicly insured US population), and in older adults (65+ years), antipsychotic use ranged from 19.0/1000 (Colombia) to 149.0/1000 (Taiwan). Atypical antipsychotic use increased in all populations (range of atypical/typical ratio: 0.7 (Taiwan) to 6.1 (New Zealand, Australia)). Quetiapine, risperidone, and olanzapine were most frequently prescribed. Prevalence and patterns of antipsychotic use varied markedly between countries. In the majority of populations, antipsychotic utilisation and especially the use of atypical antipsychotics increased over time. The high rates of antipsychotic prescriptions in older adults and in youths in some countries merit further investigation and systematic pharmacoepidemiologic monitoring.

To examine changes in annual patterns of psychotropic medication use in Australia from 2007 to 2015.We used a 10% sample of individual-level nationwide dispensing claims for concessional beneficiaries dispensed psychotropic medications (stratified by class, subclass) to investigate annual trends and changes in the incidence and prevalence of use, median annual duration of exposure, proportion of people with single psychotropic dispensing and median defined daily doses per person dispensed each medicine per year.Over the study period, there was a 26.1% decrease in the incidence and a 2.6% increase in the prevalence of all psychotropic medicine use. We observed a decrease in the annual incidence and prevalence of antidepressants (11.6% and 16.8%, respectively) but increases in the median annual duration of exposure (7.4%). Amitriptyline had the highest proportion of single dispensings of all antidepressants throughout the study period (26.5% in 2015) and defined daily doses per person dispensed each medicine per year increased by 20% for antidepressants overall. Benzodiazepine use decreased across all measures over the study period apart from long-term use (exposure for240 days of the year), which in 2015 was 23.6% of those dispensed a benzodiazepine. We observed a relative increase in the incidence and prevalence of antipsychotic use (14.2% and 26.8%, respectively), and haloperidol had the highest proportion of single dispensings of any antipsychotic throughout the study period (47.5% in 2015). We observed a relative increase in the incidence and prevalence of attention-deficit hyperactivity disorder medication use of 114.0% and 101.8%, respectively, over the study period.Increasing doses and treatment durations of antidepressants warrants further investigation due to concerns about overuse. Single dispensings of amitriptyline and haloperidol may indicate off-label use and long-term use of benzodiazepines remains problematic. Despite increases in attention-deficit hyperactivity disorder medication use, prevalence of use is still much lower than the estimated prevalence of attention-deficit hyperactivity disorder in the adult population.

Objective To describe and analyse factors associated with natural birth intentions in a sample of pre-pregnant Icelandic women. Methods An internationally validated tool was used to survey pre-pregnant women about their attitudes towards birth. The online survey was sent to all students at the University of Iceland in November 2014. Log binomial regression was used to calculate crude and adjusted relative risks (RR a ), and corresponding 95% confidence intervals (CI), for intentions of natural birth (defined as vaginal birth without epidural analgesia) by high, moderate and low childbirth fear and by high, moderate and low confidence in birth knowledge. Models were adjusted for socio-demographic and psychological factors. Results 410 eligible women completed the cross-sectional survey. Women with low fear of birth were more likely to have natural birth intentions when compared to women with moderate (RR a = 2.83; 95% CI; 1.48–5.41) and high (RR a = 4.86; 95% CI; 1.37–17.27) fear. Women with high confidence in their birth knowledge were more likely to have natural birth intentions compared to women with moderate (RR a = 2.81; 95% CI; 1.51–5.22) and low (RR a = 3.42; 95% CI; 1.43–8.18) confidence in their birth knowledge. Conclusion Pre-pregnant women with low fear of birth and high confidence in their birth knowledge are more likely to have natural birth intentions. Addressing concerns about pain, safety, the perceived unpredictability of birth and worries about the physical impact of childbirth may strengthen natural birth intentions.

Publisher's version (útgefin grein), 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., This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies (NorPreSS) (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366). Linkage of Danish data was supported by the Danish Council for Independent Research (Project No: DFF‐6110‐00019) and Karen Elise Jensens Fond (2016), and grant NNF18OC0052029 from Novo Nordisk Fonden (Li). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). We thank Anders Engeland (Norwegian Institute of Public Health, University of Bergen, Norway), Anna Heino (National Institute for Health and Welfare, Finland), Mette Nørgaard (Aarhus University, Denmark), Pär Karlsson (Karolinska Institutet, Sweden), Jennifer Yland (Harvard T.H. Chan School of Public Health, USA), Gregory Brill and Helen Mogun (Brigham and Women's Hospital & Harvard Medical School, USA) for providing assistance with analyses. The authors would like to thank the NSW Ministry of Health, the Australian Government Department of Health and Ageing and the Department of Human Services for providing data. The authors also thank the Centre for Health Record Linkage (CHeReL) and the Australian Institute for Health and Welfare for conducting the linkage of records.

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 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 (DDD)/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 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. This article is protected by copyright. All rights reserved.

Publisher's version (útgefin grein)., Objective Diabetes in pregnancy and consequently the need for treatment with antidiabetic medication (ADM) has become increasingly prevalent. The prevalence and patterns of use of ADM in pregnancy from 2006 onward in seven different countries was assessed. Research design and methods Data sources included individually linked data from the nationwide health registers in Denmark (2006-2016), Finland (2006-2016), Iceland (2006-2012), Norway (2006-2015), Sweden (2006-2015), state-wide administrative and claims data for New South Wales, Australia (2006-2012) and two US insurance databases: Medicaid Analytic eXtract (MAX; 2006-2012, public) and IBM MarketScan (2012-2015, private). The prevalence of ADM use was calculated as the proportion of pregnancies with at least one filled prescription of an ADM in the 90 days before pregnancy or within the three trimesters of pregnancy. Results Prevalence of any ADM use in 5 279 231 pregnancies was 3% (n=147 999) and varied from under 2% (Denmark, Norway, and Sweden) to above 5% (Australia and US). Insulin was the most used ADM, and metformin was the most used oral hypoglycemic agent with increasing use over time in all countries. In 11.4%-62.5% of pregnancies with prepregnancy use, ADM (primarily metformin) was discontinued. When ADM treatment was initiated in late pregnancy for treatment of gestational diabetes mellitus, insulin was most often dispensed, except in the US, where glibenclamide was most often used. Conclusions Prevalence and patterns of use of ADM classes varied between countries and over time. While insulin remained the most common ADM used in pregnancy, metformin use increased significantly over the study period., g This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies project (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366) both awarded to KF at Norwegian Institute of Public Health (NIHP). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). GB was supported by the Swedish Society of Medicine (InPreSS grant) and the Stockholm County Council (clinical postdoctoral appointment). HZ was funded by a Scientia Fellowship awarded by UNSW. BTB, SH-D and KFH were supported by the grant R01HD097778 from the Eunice Kennedy Shriver National Institute for Child Health & Human Development. YY’s salary is paid by unrestricted grants from the Lundbeck Foundation (R232-2016-2462 and R265-2017-4069), unrelated to this work. The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.

Background Studies describing the incidence of Crohn's disease (CD) and ulcerative colitis (UC) are uncommon in the United States. We sought to determine the incidence of CD and UC in the state of Rhode Island. Methods The Ocean State Crohn's and Colitis Area Registry is a state-based inception cohort of patients newly diagnosed with inflammatory bowel disease (IBD) in Rhode Island. To confirm a diagnosis of CD, UC, or IBD unclassified (IBDU), the National Institute of Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium criteria were applied in a review of medical records from gastroenterology practices located in the state of Rhode Island and adjacent to the Rhode Island border in Massachusetts and Connecticut. Using population-based data, we determined the statewide incidence of IBD in Rhode Island from 2008 to 2010. Results A total of 971 Rhode Island residents were diagnosed with IBD, including 444 with CD, 486 with UC, and 41 with IBD unclassified from 2008 to 2010. The overall age- and sex-adjusted IBD incidence was 30.2 (95% confidence interval, 28.3-32.1) per 100,000 persons in this time frame with 13.9, 15.1, and 1.3 per 100,000 diagnosed with CD, UC, and IBD unclassified, respectively. Of the total incident cases in Rhode Island, 30% (n = 291) were enrolled in Ocean State Crohn's and Colitis Area Registry for follow-up. Conclusions The incidence of IBD in Rhode Island is higher than that previously reported by other population-based cohorts in the United States. Prospective follow-up of individuals enrolled in the community-based Ocean State Crohn's and Colitis Area Registry cohort is ongoing.

Although smoking during pregnancy may lead to many adverse outcomes, numerous studies have reported a paradoxical inverse association between maternal cigarette smoking during pregnancy and preeclampsia. Using a counterfactual framework we aimed to explore the structure of this paradox as being a consequence of selection bias. Using a case-control study nested in the Icelandic Birth Registry (1309 women), we show how this selection bias can be explored and corrected for. Cases were defined as any case of pregnancy induced hypertension or preeclampsia occurring after 20 weeks' gestation and controls as normotensive mothers who gave birth in the same year. First, we used directed acyclic graphs to illustrate the common bias structure. Second, we used classical logistic regression and mediation analytic methods for dichotomous outcomes to explore the structure of the bias. Lastly, we performed both deterministic and probabilistic sensitivity analysis to estimate the amount of bias due to an uncontrolled confounder and corrected for it. The biased effect of smoking was estimated to reduce the odds of preeclampsia by 28 % (OR 0.72, 95 %CI 0.52, 0.99) and after stratification by gestational age at delivery (37 vs. ≥37 gestation weeks) by 75 % (OR 0.25, 95 %CI 0.10, 0.68). In a mediation analysis, the natural indirect effect showed and OR 1, revealing the structure of the paradox. The bias-adjusted estimation of the smoking effect on preeclampsia showed an OR of 1.22 (95 %CI 0.41, 6.53). The smoking-preeclampsia paradox appears to be an example of (1) selection bias most likely caused by studying cases prevalent at birth rather than all incident cases from conception in a pregnancy cohort, (2) omitting important confounders associated with both smoking and preeclampsia (preventing the outcome to develop) and (3) controlling for a collider (gestation weeks at delivery). Future studies need to consider these aspects when studying and interpreting the association between smoking and pregnancy outcomes.

Publisher's version (útgefin grein), Background The global Choosing Wisely campaign has identified the following psychotropic prescribing as low-value (harmful or wasteful): (1) benzodiazepine use in the elderly, (2) antipsychotic use in dementia and (3) prescribing two or more antipsychotics concurrently. We aimed to quantify the extent of these prescribing practices in the Australian population. Methods We applied indicators to dispensing claims of a 10% random sample of Australian Pharmaceutical Benefits Scheme beneficiaries to quantify annual rates of each low-value practice from 2013 to 2016. We also assessed patient factors and direct medicine costs (extrapolated to the entire Australian population) associated with each practice in 2016. Results We observed little change in the rates of the three practices between 2013 and 2016. In 2016, 15.3% of people aged ≥65 years were prescribed a benzodiazepine, 0.5% were prescribed antipsychotics in the context of dementia and 0.2% of people aged ≥18 years received two or more antipsychotics concurrently. The likelihood of elderly people receiving benzodiazepines or antipsychotics in the context of dementia increased with age and the likelihood of receiving all three practices increased with comorbidity burden. In 2016, direct medicine costs to the government of all three practices combined, extrapolated to national figures, were > $21 million AUD. Conclusions Our indicators suggest that the frequency of these three practices has not changed appreciably in recent years and that they incur significant costs. Worryingly, people with the greatest risk of harm from these prescribing practices are often the most likely to receive them., This research was supported by the National Health and Medical Research Council (NHMRC) Centre for Research Excellence in Medicines and Ageing (CREMA), a Project Grant for measuring low-value care for targeted policy action and JB received funding support from an NHMRC Postgraduate award. These funding bodies played no role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript.

Publisher's version (útgefin grein), Background Hypertensive disorders complicate up to 10% of pregnancies. Evidence suggests a potential association between maternal hypertensive disorders during pregnancy, particularly preeclampsia, and adverse neurodevelopment in the offspring, but existing studies are subject to limitations. We aimed to assess whether in-utero exposure to preeclampsia/eclampsia negatively impacts academic performance at ages 9, 12 and 15 years. Methods Using individually linked, nationwide data from the Icelandic registries we followed all children born in 1989–2004 (N = 68,580), from birth until the end of 2014, thereof 63,014 (91.9%) took at least one standardized test. Using a stepwise, mixed-effects approach, we modelled the hypothesized relationship while adjusting for maternal, perinatal and childhood variables of interest. We compared test scores, measured on a normalized scale ranging from 0–60 with a mean of 30 and a standard deviation of 10, in the 4th, 7th, and 10th grades, between children exposed to preeclampsia or eclampsia in-utero versus children from normotensive pregnancies in the population. Results Children exposed to preeclampsia/eclampsia scored lower than those unexposed in mathematics across all grade levels, corresponding to a difference of 0.44 points (95% CI: 0.00, 0.89), 0.59 points (95% CI: 0.13, 1.06) and 0.59 points (95% CI: 0.08, 1.10), respectively. No differences were observed in the language arts. Conclusions Our findings suggest a minimal effect of maternal preeclampsia/eclampsia on children’s academic performance at ages 9, 12 and 15 years. The differences observed in mathematic scores between exposed and unexposed children were minimal, less than one tenth of a standard deviation per measurement occasion., HZ received financial support for this study from the Icelandic Centre for Research, START – Reintegration fellowship, under Award Number 130814-051, http://www.rannis.is. BTB was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (Bethesda, Maryland, United States) under Award Number K08HD075831. Dr. Helga Zoega was supported by a Scientia Fellowship awarded by the University of New South Wales. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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.

Paracetamol (acetaminophen) is one of the most commonly used analgesics in Europe; however, both the safety and efficacy of paracetamol have recently been questioned. Little is known about cross-national differences in the sales of paracetamol. Using national wholesale statistics and nationwide prescription drug registers, we investigated trends in total and prescribed use of paracetamol in the Nordic countries. The total sales of paracetamol (Anatomical Therapeutic Chemical (ATC) classification system code: N02BE01) measured as defined daily doses (DDD) per 1000 inhabitants/day, and the sales by prescription (users per 1000 inhabitants/year), increased in the Nordic countries from 2000 to 2015. The total sales were highest in Denmark throughout the period, with 65 DDD per 1000 inhabitants/day and lowest in Iceland with 30 DDD per 1000 inhabitants/day in 2015. The cross-national difference in total sales of paracetamol was smaller in 2015 than in 2000. The proportion of paracetamol (DDD per 1000 inhabitants/day) sold by prescription was also highest in Denmark (78%), compared with 75% in Finland, 69% in Sweden, 61% in Norway and 38% in Iceland. Paracetamol by prescription was more common at older ages and among women. Total and prescribed sales of paracetamol have increased in all five Nordic countries over time. Cross-national differences exist, with highest sales per capita in Denmark throughout the period.

Objective: There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis.Method: A repeated cross-sectional design was applied to data extracts (2005-2014) from 17 countries worldwide.Results: In 2014, overall clozapine use prevalence was greatest in Finland (189.2/100 000 persons) and in New Zealand (116.3/100 000), and lowest in the Japanese cohort (0.6/100 000), and in the privately insured US cohort (14.0/100 000). From 2005 to 2014, clozapine use increased in almost all studied countries (relative increase: 7.8-197.2%). In most countries, clozapine use was highest in 40-59-year-olds (range: 0.6/100 000 (Japan) to 344.8/100 000 (Finland)). In youths (1019 years), clozapine use was highest in Finland (24.7/100 000) and in the publicly insured US cohort (15.5/100 000).Conclusion: While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation.

SummaryBackground Fatigue is common in Crohn's disease (CD) and ulcerative colitis (UC). Data on fatigue in newly diagnosed patients are unavailable. Aim To report prevalence of fatigue in newly diagnosed CD and UC patients and examine its association with health-related quality of life (HRQOL), depression and disability. Methods The Ocean State Crohn's and Colitis Area Registry (OSCCAR) is a statewide cohort of newly diagnosed inflammatory bowel disease patients in Rhode Island. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue Scale. Patients were administered instruments measuring HRQOL, overall disability and work impairment, and depression. Results Fatigue was prevalent in 26.4% of 220 subjects. Cohen's d effect sizes for fatigue were large: Short-Form 36 Health Survey mental health component (CD 1.5, UC 1.4) and physical health component (CD 1.4, UC 1.4), EuroQol-5D valuation of current health state (CD 1.2, UC 1.0), Inflammatory Bowel Disease Questionnaire (CD 1.9, UC 1.6) and Patient Health Questionnaire depression scale (CD 1.8, UC 1.7). Fatigued patients reported more work impairment (Score difference: CD 29.5%, UC 23.8%) and activity impairment (score difference: CD 32.3%, UC 25.7%) on the Work Productivity and Activity Impairment Questionnaire. Fatigue's association with all scores remained highly significant despite controlling for disease activity. Conclusions Fatigue is strongly associated with poor HRQOL, disability and depression similarly in CD and UC even when controlling for disease activity. Fatigue's association with a wide range of patient-reported outcome measures suggests that monitoring fatigue is a simple way to screen for overall disruption in patient life.

Purpose The use of ADHD drugs among adults is controversial and has until recently not been approved for use in adults in most countries. The aim was to investigate use of ADHD drugs (stimulants and atomoxetine) among the entire adult population in the Nordic countries. Methods We conducted a multinational population-based prescription register study based on the entire adult population in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). All users of ADHD drugs aged 18–64 years during 2008–2012 were included, which for 2012 comprised 76,896 drug users among 15.8 million adult inhabitants. Results Annual prevalence of drug use increased during the study period for both genders and all age groups. The overall prevalence increased from 2.4 to 5.3 per 1000 men and 1.8 to 4.4 per 1000 women. Incidence also increased, but to a lesser extent in the last part of the study period. Methylphenidate was used by 88 % of drug users. Treatment was discontinued within the first year by 21 % of new drug users. Among all users of ADHD drugs, 53 % of men and 64 % of women concurrently used other psychotropic drugs, most frequently antidepressants and hypnotics. Psychotropic co-medication increased with age and was more pronounced among women than men. Conclusions Use of ADHD drug among adults more than doubled over a 5-year period, and a majority were concurrently treated with other psychotropics. Adults constitute a substantial proportion of persons treated with ADHD drugs. Thus, evidence for long-term efficacy and safety in adults is urgently needed. Electronic supplementary material The online version of this article (doi:10.1007/s00228-016-2125-y) contains supplementary material, which is available to authorized users.

OBJECTIVE: To assess whether use of specific selective serotonin reuptake inhibitors (SSRIs) or venlafaxine in early pregnancy is associated with an increased risk of birth defects, with emphasis on cardiovascular birth defects even when accounting for lifestyle or other familial confounding. DESIGN: Multicountry population based cohort study, including sibling controlled design. SETTING: Nordic population (Denmark, Finland, Iceland, Norway, and Sweden) identified from nationwide health registers at different periods in 1996-2010. POPULATION: The full study cohort included women giving birth to 2.3 million live singletons. The sibling cohort included 2288 singleton live births. The sibling controlled analyses included sibling pairs who were discordant for exposure to SSRIs or venlafaxine and birth defects. MAIN OUTCOME MEASURE: Prevalence of birth defects, including subtypes of cardiac defects. Odds ratio of birth defects from logistic and conditional logistic regression. RESULTS: Among 36,772 infants exposed to any SSRI in early pregnancy, 3.7% (n=1357) had a birth defect compared with 3.1% of 2,266,875 unexposed infants, yielding a covariate adjusted odds ratio of 1.13 (95% confidence interval 1.06 to 1.20). In the sibling controlled analysis the adjusted odds ratio decreased to 1.06 (0.91 to 1.24). The odds ratios for any cardiac birth defect with use of any SSRI or venlafaxine were 1.15 (95% confidence interval 1.05 to 1.26) in the covariate adjusted analysis and 0.92 (0.72 to 1.17) in the sibling controlled analysis. For atrial and ventricular septal defects the covariate adjusted odds ratio was 1.17 (1.05 to 1.31). Exposure to any SSRI or venlafaxine increased the prevalence of right ventricular outflow tract obstruction defects, with a covariate adjusted odds ratio of 1.48 (1.15 to 1.89). In the sibling controlled analysis the adjusted odds ratio decreased to 0.56 (0.21 to 1.49) for any exposure to SSRIs or venlafaxine and right ventricular outflow tract obstruction defects. CONCLUSIONS: In this large Nordic study no substantial increase was found in prevalence of overall cardiac birth defects among infants exposed to SSRIs or venlafaxine in utero. Although the prevalence of septal defects and right ventricular outflow tract defects was higher in exposed infants, the lack of an association in the sibling controlled analyses points against a teratogenic effect of these drugs. publishedVersion

Background : The prevalence of smoking during pregnancy in Western societies has decreased in the last decades, whereas prevalence of overweight and obesity has increased. Our objective was to study secular trends and patterns of smoking and body weight among pregnant women in Iceland, during a period of dramatic changes in the nation’s economy. Methods : On the basis of the Medical Birth Registry, we used a random sample of 1329 births between 1 January 2001 and 31 December 2010. Information on smoking, body mass index and background factors during pregnancy was retrieved from the Medical Birth Register and maternity records. Trends in smoking, overweight, obesity and body mass index were assessed using logistic and linear regression analyses. Logistic regression analysis was used to examine the annual odds of smoking and obesity and by socio-demographic characteristics. Results : We found a decrease in the prevalence of continued smoking during pregnancy from 12.4% in 2001 to 7.9% in 2010 [odds ratio (OR) = 0.94, 95% confidence interval (CI) (0.88–1.00)], particularly among women with Icelandic citizenship [OR = 0.92, 95% CI (0.86–0.98)], whereas no changes in obesity [OR = 1.02, 95% CI (0.96–1.07)] were observed. The highest prevalence of maternal smoking and obesity was observed in 2005–06. Conclusion : Our results indicate that smoking during pregnancy decreased among Icelandic women in 2001–10, whereas an initial increase in obesity prevalence seemed to level off towards the end of the observation period. Interestingly, we found that both of these maternal risk factors reached their highest prevalence in 2005–06, which coincides with a flourishing period in the nation’s economy.

Knowledge of patterns of treatment discontinuation in attention-deficit/hyperactivity disorder (ADHD) drug treatment is of importance, for both the clinical practice and the study of long-term treatment outcomes. The purpose of this study was to describe early discontinuation of ADHD drug treatment. Using the Danish National Prescription Registry, all first-time users of the ADHD drugs methylphenidate and atomoxetine were identified between 2000 and 2012. Early discontinuation was defined as failing to fill a second prescription for any ADHD drug within 6 months. Analyses were conducted stratified by calendar year, drug formulation, patient sex, age and region of residence. 59,116 first-time users of methylphenidate and atomoxetine with at least 6 months of eligible follow-up were identified. Overall, 12.6% (n = 7441) failed to fill a second prescription within 6 months. This proportion changed over time, dropping from 20.8% in 2000 to 12.5% in 2012. The proportion of early discontinuation was considerably lower among children than among adults. Proportions were comparable when stratifying by index drug. Proportions of early discontinuation were similar between regions of Denmark, except in the capital region, where it remained at around 20% among 18- to 49-year-olds throughout the study period (22.6% in 2012). In conclusion, we found that the proportion of early discontinuation among ADHD drug users in Denmark dropped markedly during the past decade for both sexes, all age groups and all regions, except for adults in the capital region. Overall, early discontinuation was somewhat lower than expected, considering rates of side effects or non-response to ADHD drug treatment.

BACKGROUND: The purpose was to describe utilization of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including trends in prevalence, characteristics of users, drug switching and changes in prescribed doses in a large group of pregnant women across four Nordic countries.METHODS: A drug utilization study based on linked individual-level data from the nationwide prescription- and medical birth registers in Denmark, Iceland, Norway and Sweden. The study population comprised all pregnancies in these countries, resulting in a live birth or stillbirth after gestational week 22 from January 1st 2008 to December 31st 2012 (N = 1 162 470). In addition to the main study drugs SSRIs and SNRIs, we included (concurrent) use of other antidepressants, antipsychotics, anxiolytics and hypnotics.RESULTS: A total of 38 219 (3.3%) pregnancies were exposed to SSRIs and 5 634 (0.5%) to SNRIs. Prevalence of SSRI and SNRI use varied by country (1.8% in Norway to 7.0% in Iceland). Use and prescribed dosages decreased with each passing trimester of pregnancy; prevalence was 2.7% at conception, and 2.1%, 1.7% and 1.3% respectively in 1st, 2nd and 3rd trimester. In 0.6% of pregnancies women filled a prescription before pregnancy and in every trimester. In one third of exposed pregnancies, women were also dispensed anxiolytics, hypnotics or sedatives.CONCLUSION: Use of SSRI and SNRI use during pregnancy varied between the Nordic countries, but the overall prevalence remained low and relatively stable from 2008 to 2012. The low prevalence of use and high proportion of women who discontinue treatment in pregnancy raise questions about adequate treatment of depression in pregnant women.

Objective To assess whether the use of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, mirtazapine, venlafaxine or other antidepressants is associated with late elective termination of pregnancy. Design Case–control study using data from national registers. Setting Denmark, Finland, and Norway during the period 1996–2007. Population A total of 14 902 women were included as cases and 148 929 women were included as controls. Methods Cases were women with elective termination of pregnancy at 12–23 weeks of gestation. Controls continued their pregnancy and were matched with cases on key factors. Main outcome measures Association between antidepressant use during pregnancy and elective termination of pregnancy at 12–23 weeks of gestation for fetal anomalies, or for maternal ill health or socio-economic disadvantage. Results At least one prescription of antidepressants was filled by 3.7% of the cases and 2.2% of the controls. Use of any type of antidepressant was associated with elective termination of pregnancy for maternal ill health or socio-economic disadvantage (odds ratio, OR 2.3; 95% confidence interval, 95% CI 2.0–2.5). Elective termination of pregnancy for fetal anomalies was associated with the use of mirtazapine (OR 2.2, 95% CI 1.1–4.5). There was no association between the use of any of the other antidepressants and elective termination of pregnancy for fetal anomalies. Conclusion The use of any type of antidepressants was associated with elective termination of pregnancy at 12–23 weeks for maternal ill health or socio-economic disadvantage, but not with terminations for fetal anomalies. Further studies need to confirm the findings concerning mirtazapine and termination of pregnancy for fetal anomalies.

Background Data on the potential influence of macroeconomic recessions on maternal diseases during pregnancy are scarce. We aimed to assess potential change in prevalence of pregnancy-induced hypertensive disorders (preeclampsia and gestational hypertension) during the first years of the major national economic recession in Iceland, which started abruptly in October 2008. Methods and Findings Women whose pregnancies resulted in live singleton births in Iceland in 2005–2012 constituted the study population (N = 35,211). Data on pregnancy-induced hypertensive disorders were obtained from the Icelandic Medical Birth Register and use of antihypertensive drugs during pregnancy, including β-blockers and calcium channel blockers, from the Icelandic Medicines Register. With the pre-collapse period as reference, we used logistic regression analysis to assess change in pregnancy-induced hypertensive disorders and use of antihypertensives during the first four years after the economic collapse, adjusting for demographic and pregnancy characteristics, taking aggregate economic indicators into account. Compared with the pre-collapse period, we observed an increased prevalence of gestational hypertension in the first year following the economic collapse (2.4% vs. 3.9%; adjusted odds ratio [aOR] 1.47; 95 percent confidence interval [95%CI] 1.13–1.91) but not in the subsequent years. The association disappeared completely when we adjusted for aggregate unemployment rate (aOR 1.04; 95% CI 0.74–1.47). Similarly, there was an increase in prescription fills of β-blockers in the first year following the collapse (1.9% vs.3.1%; aOR 1.43; 95% CI 1.07–1.90), which disappeared after adjusting for aggregate unemployment rate (aOR 1.05; 95% CI 0.72–1.54). No changes were observed for preeclampsia or use of calcium channel blockers between the pre- and post-collapse periods. Conclusions Our data suggest a transient increased risk of gestational hypertension and use of β-blockers among pregnant women in Iceland in the first and most severe year of the national economic recession.

In this study, we leveraged on complete nationwide prescription data for the total adult population in Iceland (N = 227,000) to examine how attention-deficit/hyperactivity disorder (ADHD) drugs have been used over the past decade. In particular, we aimed to describe the prevalence, incidence and duration of use of stimulants and atomoxetine, among adults (≥19 years) in Iceland, with regard to sex, age, type of drug and specialty of the prescribing physician. Our results indicate that the 1-year period prevalence of ADHD drug use rose, from 2.9 to 12.2 per 1000 adults between 2003 and 2012, with the most pronounced increases among young adults (19-24 years). The annual incidence increased 3 times, similarly among men and women. Extended-release methylphenidate formulations were the most commonly used ADHD drugs. Specialists in psychiatry initiated treatment in 79% of new adult ADHD drug users. The proportion of users still receiving treatment after 1 year varied from 43.0% (19-24 years), 57.2% (25-49 years) to 47.5% (50+ years). After 3 years, the corresponding proportions still on treatment were 12.4%, 24.5% and 24.3%, and after 5 years 7.9%, 15.9% and 16.8%. These results of increasing ADHD drug use and short treatment durations call for further investigation of the quality of treatment regimens for adults with ADHD and better follow-up of patients treated with ADHD drugs. Primarily used in treatment of children with attention-deficit/ hyperactivity disorder (ADHD), stimulants are in growing use among adults in many Western countries (1-13). According to both clinical guidelines issued by the National Institute for Health and Clinical Excellence (14) and the consensus state- ment by the European Network Adult ADHD (15), pharmaco- therapy should be the first-line treatment for adults with ADHD. Stimulants such as methylphenidate should be the first-choice treatment option and the non-stimulants atomoxe- tine as second choice. Yet, in 2013, the approval of stimulant and non-stimulant pharmacotherapy for adults with ADHD was very limited both within the EU and outside (16,17). Cur- rently, in 2014, only three countries within the EU have approved medications for treatment of newly diagnosed adult ADHD patients, that is methylphenidate in Germany (18,19) and atomoxetine in the UK and Denmark (20-22), causing a mixed message and conflicting directives to the public. The controversy of how to treat ADHD in adults is rooted in a debate of the validity of underlying diagnoses (3,15,23-28), as well as in concerns of potential misuse of the drugs (29). Previous research shows that overall use of stimulants and atomoxetine in Iceland is up to five times the use in other Nordic countries (4), at a similar rate as has been reported within the United States (30). Recently, the International Nar- cotics Control Board (INCB) issued a warning to the Icelandic government expressing concern over the amounts of sold stim- ulants in Iceland (29). Very little is known about the patterns of drug utilization for ADHD among adults. A few studies have combined descriptions of paediatric and adult treatment (3,4,9,12,13,31), but none of these focus specifically on treatment patterns in the adult population.

Importance Maternal psychiatric disease is associated with adverse pregnancy outcomes. Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy has been associated with congenital anomalies, neonatal withdrawal syndrome, and persistent pulmonary hypertension of the newborn. However, the risk of stillbirth and infant mortality when accounting for previous maternal psychiatric disease remains unknown. Objective To study risk of stillbirth and infant mortality associated with use of SSRIs during pregnancy. Design, Setting, and Participants Population-based cohort study from all Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) at different periods from 1996 through 2007. The study included women with singleton births. We obtained information on maternal use of SSRIs from prescription registries. Maternal characteristics, pregnancy, and neonatal outcomes were obtained from patient and medical birth registries. Main Outcome Measures We used logistic regression to estimate relative risks of stillbirth, neonatal death, and postneonatal death associated with SSRI use during pregnancy taking into account maternal characteristics and previous psychiatric hospitalization. Results Among 1 633 877 singleton births in the study, 6054 were stillbirths; 3609, neonatal deaths; and 1578, postneonatal deaths. A total of 29 228 (1.79%) of mothers had filled a prescription for an SSRI during pregnancy. Women exposed to an SSRI presented with higher rates of stillbirth (4.62 vs 3.69 per 1000, P = .01) and postneonatal death (1.38 vs 0.96 per 1000, P = .03) than those who did not. The rate of neonatal death was similar between groups (2.54 vs 2.21 per 1000, P = .24). Yet in multivariable models, SSRI use was not associated with stillbirth (adjusted odds ratio [OR], 1.17; 95% CI, 0.96-1.41; P = .12), neonatal death (adjusted OR, 1.23; 95% CI, 0.96-1.57; P = .11), or postneonatal death (adjusted OR, 1.34; 95% CI, 0.97-1.86; P = .08). Estimates were further attenuated when stratified by previous hospitalization for psychiatric disease. The adjusted OR for stillbirth in women with a previous hospitalization for psychiatric disease was 0.92 (95% CI, 0.66-1.28; P = .62) and was 1.07 (95% CI, 0.84-1.36; P = .59) for those who had not been previously hospitalized. The corresponding ORs for neonatal death were 0.89 (95% CI, 0.58-1.39; P = .62) for women who were hospitalized and 1.14 (95% CI, 0.84-1.56; P = .39) for women who were not. For postneonatal death, the ORs were 1.02 (95% CI, 0.61-1.69; P = .95) for women who were hospitalized and 1.10 (95% CI, 0.71-1.72; P = .66) for women who were not. Conclusions and Relevance Among women with singleton births in Nordic countries, no significant association was found between use of SSRIs during pregnancy and risk of stillbirth, neonatal mortality, or postneonatal mortality. However, decisions about use of SSRIs during pregnancy must take into account other perinatal outcomes and the risks associated with maternal mental illness.

While obesity is an indicated risk factor for hypertensive disorders of pregnancy, smoking during pregnancy has been shown to be inversely associated with the development of preeclampsia and gestational hypertension. The purpose of this study was to investigate the combined effects of high body mass index and smoking on hypertensive disorders during pregnancy. This was a case-control study based on national registers, nested within all pregnancies in Iceland 1989-2004, resulting in birth at the Landspitali University Hospital. Cases (n = 500) were matched 1:2 with women without a hypertensive diagnosis who gave birth in the same year. Body mass index (kg/m2) was based on height and weight at 10-15 weeks of pregnancy. We used logistic regression models to calculate odds ratios and corresponding 95% confidence intervals as measures of association, adjusting for potential confounders and tested for additive and multiplicative interactions of body mass index and smoking. Women's body mass index during early pregnancy was positively associated with each hypertensive outcome. Compared with normal weight women, the multivariable adjusted odds ratio for any hypertensive disorder was 1.8 (95% confidence interval, 1.3-2.3) for overweight women and 3.1 (95% confidence interval, 2.2-4.3) for obese women. The odds ratio for any hypertensive disorder with obesity was 3.9 (95% confidence interval 1.8-8.6) among smokers and 3.0 (95% confidence interval 2.1-4.3) among non-smokers. The effect estimates for hypertensive disorders with high body mass index appeared more pronounced among smokers than non-smokers, although the observed difference was not statistically significant. Our findings may help elucidate the complicated interplay of these lifestyle-related factors with the hypertensive disorders during pregnancy.

Summary Objectives To evaluate the effect of an integrated hatha yoga practice on perceived stress and stress-related symptoms in the aftermath of an earthquake. Design and setting Inhabitants, aged 20–67 years, from highly exposed earthquake areas of two villages in South Iceland were offered to participate in a yoga program subsequent to an earthquake. Sixty-six individuals were self-selected into the study and divided by residential convenience into an experimental group ( n =31) and a waiting list control group ( n =35). Intervention The yoga program was conducted twice a week for six weeks, in normal situations among the inhabitants in the community. Main outcome measures Several validated questionnaires assessing stress and stress-related symptoms, posttraumatic symptoms, depression, anxiety and health related quality of life were administered at pre- and post-intervention. Results Multivariate analysis of variance (MANOVA) revealed differences between the experimental group and waiting list control group on sleep quality ( p =.03) and social relations ( p =.04). These differences did not prevail at Bonferroni correction for multiple testing (at alpha level of .005). Participants in both groups showed significant improvements in stress and some stress-related symptoms such as sleep, concentration, well-being, quality of life, depression and anxiety from pre- to post-intervention. Conclusions The data from this small study show no statistically significant improvement of an integrated hatha yoga program above and beyond waiting list control, following exposure to an earthquake. However, the observed trend toward improved sleep quality and social relations deserve further exploration in larger effectiveness studies on the impact of Hatha yoga on recovery after natural disaster.

OBJECTIVE: To assess whether maternal use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of persistent pulmonary hypertension in the newborn, and whether such an effect might differ between specific SSRIs. DESIGN: Population based cohort study using data from the national health registers. SETTING: Denmark, Finland, Iceland, Norway, and Sweden, 1996-2007. PARTICIPANTS: More than 1.6 million infants born after gestational week 33. MAIN OUTCOME MEASURES: Risks of persistent pulmonary hypertension of the newborn associated with early and late exposure to SSRIs during pregnancy and adjusted for important maternal and pregnancy characteristics. Comparisons were made between infants exposed and not exposed to SSRIs. RESULTS: Around 30 000 women had used SSRIs during pregnancy and 11 014 had been dispensed an SSRI later than gestational week 20. Exposure to SSRIs in late pregnancy was associated with an increased risk of persistent pulmonary hypertension in the newborn: 33 of 11 014 exposed infants (absolute risk 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000); adjusted odds ratio 2.1 (95% confidence interval 1.5 to 3.0). The increased risks of persistent pulmonary hypertension in the newborn for each of the specific SSRIs (sertraline, citalopram, paroxetine, and fluoxetine) were of similar magnitude. Filling a prescription with SSRIs before gestational week 8 yielded slightly increased risks: adjusted odds ratio 1.4 (95% confidence interval 1.0 to 2.0). CONCLUSIONS: The risk of persistent pulmonary hypertension of the newborn is low, but use of SSRIs in late pregnancy increases that risk more than twofold. The increased risk seems to be a class effect. publishedVersion

Air pollutants in Iceland's capital area include hydrogen sulfide (H2S) emissions from geothermal power plants, particle pollution (PM10) and traffic-related pollutants. Respiratory health effects of exposure to PM and traffic pollutants are well documented, yet this is one of the first studies to investigate short-term health effects of ambient H2S exposure.The aim of this study was to investigate the associations between daily ambient levels of H2S, PM10, nitrogen dioxide (NO2) and ozone (O3), and the use of drugs for obstructive pulmonary diseases in adults in Iceland's capital area.The study period was 8 March 2006 to 31 December 2009. We used log-linear Poisson generalized additive regression models with cubic splines to estimate relative risks of individually dispensed drugs by air pollution levels. A three-day moving average of the exposure variables gave the best fit to the data. Final models included significant covariates adjusting for climate and influenza epidemics, as well as time-dependent variables.The three-day moving average of H2S and PM10 levels were positively associated with the number of individuals who were dispensed drugs at lag 3-5, corresponding to a 2.0% (95% confidence interval [CI] 0.4, 3.6) and 0.9% (95% CI 0.1, 1.8) per 10 μg/m3 pollutant concentration increase, respectively.Our findings indicated that intermittent increases in levels of particle matter from traffic and natural sources and ambient H2S levels were weakly associated with increased dispensing of drugs for obstructive pulmonary disease in Iceland's capital area. These weak associations could be confounded by unevaluated variables hence further studies are needed.