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Natalia Mouratidou,1,2 Petter Malmborg,2,3 Jacob Järås,2 Vignir Sigurdsson,4 Olof Sandström,5 Ulrika L Fagerberg,6,7 Gabriella Bröms,2,8 Jonas F Ludvigsson,9,10 Ola Olén2,3 On behalf of the SWIBREG Study Group1Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden; 2Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 3Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden; 4Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg and Queen Silvia’s Children’s Hospital, Gothenburg, Sweden; 5Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden; 6Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden; 7Department of Pediatrics, Centre for Clinical Research, Västmanland Hospital, Västerås, Uppsala University, Västerås, Sweden; 8Gastroenterology, Danderyds Hospital, Stockholm, Sweden; 9Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; 10Department of Pediatrics, Örebro University Hospital, Örebro, SwedenCorrespondence: Natalia Mouratidou, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden, Tel +46708108338, Fax +46812393251, Email natalia.mouratidou@ki.sePurpose: The Swedish National Patient Register (NPR) is often used in observational studies of childhood-onset inflammatory bowel disease (IBD) (< 18 years of age) and its subtypes, but the validity of previously used register-based algorithms for capturing childhood-onset IBD has never been examined.Methods: We identified a random sample of 233 individuals with at least two first ever diagnostic listings of IBD in the NPR between 2002 and 2014. We calculated the test characteristics for different register-based definitions of IBD and its subtypes using the Copenhagen criteria and the revised Porto criteria as gold standard, both based on medical chart review. We made assumptions of the occurrence of undiagnosed IBD in the general child population based on available literature.Results: Out of 233 individuals with at least two diagnostic listings of IBD, 216 had true IBD, resulting in a positive predictive value (PPV) = 93% (95% confidence interval (CI) 89– 96), sensitivity = 88% (95% CI 83– 92), specificity = 100% (95% CI 100– 100), and negative predictive value (NPV) = 100% (95% CI 100– 100). The PPV for the NPR-based definitions of IBD subtypes at time of first IBD diagnosis and at end of follow-up were 78% (95% CI 69– 86) and 88% (95% CI 80– 94), respectively, for Crohn’s disease and 74% (95% CI 63– 83) and 71% (95% CI 60– 80), respectively, for ulcerative colitis.Conclusion: The validity of register-based definitions of childhood-onset IBD in the Swedish NPR is high and can be used to identify patients in observational research.Keywords: health administrative data, Crohn’s disease, ulcerative colitis, disease progression, diagnostic delay

Lukas Löfling, Gabriella Bröms, Shahram Bahmanyar, Helle Kieler Department of Medicine, Solna Centre for Pharmacoepidemiology (CPE), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Background: Data from the Nordic health care registers have been of great value in perinatal epidemiological research. It has been assumed that findings from the Nordic population (Denmark, Finland, Iceland, Norway, and Sweden) are applicable to other populations as well, including the population of the US.Objective: To describe and compare maternal and infant characteristics between the Nordic and the American populations as recorded in the official statistics.Materials and methods: This population-based study included data on all females who gave birth and their infants in the Nordic countries and the US. The data were obtained from the US National Center for Health Statistics and the official statistics data for the Nordic countries. The data from all six countries included births from 2006 to 2010.Results: The mean maternal age at delivery was lower in the US than in the Nordic countries (27.5 vs 30.3 years). Cesarean sections (32.2% vs 17.9%), low birth weight (8.2% vs 4.8%), and preterm birth (12.3% vs 5.9%) were more common in the US than in the Nordic countries. Smoking during early pregnancy was slightly less common in the US compared with Nordic countries (9.8% vs 11.2%). Restricting the data from the US to females with a university degree, characteristics such as age at delivery, birth weight, and preterm deliveries were more in alignment with the Nordic data.Conclusion: There are differences in some key maternal and neonatal characteristics between the Nordic countries and the US. However, some characteristics are related to socioeconomic status, suggesting that the Nordic data seem to be applicable to the part of the population in the US with a higher socioeconomic status. Keywords: pregnancy, Nordic countries, US, health care registers

Background: There are conflicting data on the risk of acute coronary syndrome (ACS) in patients with inflammatory bowel disease (IBD). Only a few previous reports include patients diagnosed during the last decade., Aim: To assess and compare the risk of ACS between patients with IBD and the general population., Methods: In this cohort study, we used nationwide registers to identify patients diagnosed with IBD in Sweden 2003-2021. Every patient was matched by birth year, sex, calendar year and area of residence with up to 10 general population comparators. The primary outcome was incident ACS. We used semi-parametric Cox proportional hazard models to estimate hazard ratios (HRs)., Results: We identified 76,517 patients with IBD (Crohn's disease [CD], N = 22,732; ulcerative colitis [UC], N = 42,194 and IBD-unclassified, N = 11,591) and 757,141 comparators. During a median follow-up of 8 years, 2546 patients with IBD (37.5/10,000 person-years) were diagnosed with ACS compared with 19,598 (28.0/10,000 person-years) among comparators (HR 1.30; 95% confidence interval 1.24-1.35) after adjustments for confounding factors, and approximately one extra case of ACS in 100 IBD patients followed for 10 years. The highest HRs for ACS were in patients with elderly onset IBD (≥60 years) and among patients with CD or UC with extra-intestinal manifestations. No increased HRs were observed in patients diagnosed with IBD before the age of 40., Conclusion: In this contemporary cohort of patients with IBD, exposed to modern IBD care, there was an increased risk for ACS compared with individuals from the general population., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Inflammatory bowel disease (IBD) is linked to reduced female fertility, but it is unclear how fertility rates vary by histologic disease activity., Methods: Nationwide IBD cohort of Swedish women aged 15 to 44 years. We examined fertility rates during periods with vs without histologic inflammation (n = 21,046; follow-up, 1990-2016) and during periods with vs without clinical activity (IBD-related hospitalization, surgery, or treatment escalation) (n = 24,995; follow-up, 2006-2020). Accounting for sociodemographics and comorbidities, we used Poisson regression to estimate adjusted fertility rate ratios (aFRRs) for live births conceived during 12-month periods of histologic inflammation (vs histologic remission) and 3-month periods of clinically active IBD (vs quiescent IBD)., Results: During periods with vs without histologic inflammation, there were 6.35 (95% confidence interval [CI], 5.98-6.73) and 7.09 (95% CI, 6.48-7.70) live births conceived per 100 person-years of follow-up, respectively, or 1 fewer child per 14 women with 10 years of histologic inflammation (aFRR, 0.90; 95% CI, 0.81-1.00). In women with histologic inflammation, fertility was similarly reduced in ulcerative colitis (UC) (aFRR, 0.89 [95% CI, 0.78-1.02]) and Crohn's disease (CD) (aFRR, 0.86 [95% CI, 0.72-1.04]). Clinical IBD activity was associated with an aFRR of 0.76 (95% CI, 0.72-0.79) or 1 fewer child per 6 women with 10 years of clinical activity. Fertility was reduced in clinically active UC (aFRR, 0.75 [95% CI, 0.70-0.81]) and CD (aFRR, 0.76 [95% CI, 0.70-0.82]). Finally, among women with clinically quiescent IBD, histologic inflammation (vs histologic remission) was associated with reduced fertility (aFRR, 0.85 [95% CI, 0.73-0.98])., Conclusions: An association between histologic and clinical activity and reduced female fertility in CD and UC was found. Notably, histologic inflammation was also linked to reduced fertility in women with clinically quiescent IBD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inflammatory bowel disease has been linked to increasing healthcare costs, but longitudinal data on other societal costs are scarce., Aim: To assess costs, including productivity losses, in patients with prevalent Crohn's disease (CD) or ulcerative colitis (UC) in Sweden between 2007 and 2020., Methods: We linked data from national registers on all patients with CD or UC and a matched (sex, birthyear, healthcare region and education) reference population. We assessed mean costs/year in Euros, inflation-adjusted to 2020, for hospitalisations, out-patient visits, medications, sick leave and disability pension. We defined excess costs as the mean difference between patients and matched comparators., Results: Between 2007 and 2020, absolute mean annual societal costs in working-age (18-64 years) individuals decreased by 17% in CD (-24% in the comparators) and by 20% in UC (-27% in comparators), due to decreasing costs from sick leave and disability, a consequence of stricter sick leave regulations. Excess costs in 2007 were dominated by productivity losses. In 2020, excess costs were mostly healthcare costs. Absolute and excess costs increased in paediatric and elderly patients. Overall, costs for TNF inhibitors/targeted therapies increased by 274% in CD and 638% in UC, and the proportion treated increased from 5% to 26% in CD, and from 1% to 10% in UC., Conclusion: Between 2007 and 2020, excess costs shifted from productivity losses to direct healthcare costs; that is, the patients' compensation for sickness absence decreased, while society increased its spending on medications. Medication costs were driven both by expanding use of TNF inhibitors and by high costs for newer targeted therapies., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: There are little data on positioning biologics in Crohn's disease (CD)., Aims: We aimed to assess the comparative effectiveness and safety of ustekinumab vs tumour necrosis factor-alpha (anti-TNF) agents after first-line treatment with anti-TNF in CD., Methods: We used Swedish nationwide registers to identify patients with CD, exposed to anti-TNF who initiated second-line biologic treatment with ustekinumab or second-line anti-TNF therapy. Nearest neighbour 1:1 propensity score matching (PSM) was used to balance the groups. The primary outcome was 3-year drug survival used as a proxy for effectiveness. Secondary outcomes included drug survival without hospital admission, CD-related surgery, antibiotics, hospitalization due to infection and exposure to corticosteroids., Results: Some 312 patients remained after PSM. Drug survival at 3 years was 35% (95% CI 26-44%) in ustekinumab compared to 36% (95% CI 28-44%) in anti-TNF-treated patients (p = 0.72). No statistically significant differences were observed between the groups in 3-year survival without hospital admission (72% vs 70%, p = 0.99), surgery (87% vs 92%, p = 0.17), hospital admission due to infection (92% vs 92%, p = 0.31) or prescription of antibiotics (49% vs 50%, p = 0.56). The proportion of patients continuing second-line biologic therapy did not differ by reason for ending first-line anti-TNF (lack of response vs intolerance) or by type of first-line anti-TNF (adalimumab vs infliximab)., Conclusion: Based on data from Swedish routine care, no clinically relevant differences in effectiveness or safety of second-line ustekinumab vs anti-TNF treatment were observed in patients with CD with prior exposure to anti-TNF., (© 2023. The Author(s).)

Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure., Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors., Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16)., Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Background: Inflammatory bowel disease (IBD) has been linked to adverse pregnancy outcomes, but it is unclear how risks vary by histological activity., Methods: We performed a nationwide study of Swedish women diagnosed with IBD 1990-2016 and a pre-pregnancy (<12 months) colorectal biopsy with vs. without histological inflammation (1223 and 630 births, respectively). We also examined pregnancy outcomes in 2007-2016 of women with vs. without clinically active IBD (i.e., IBD-related hospitalization, surgery, or medication escalation) <12 months before pregnancy (2110 and 4993 births, respectively). Accounting for smoking, socio-demographics, and comorbidities, generalized linear models estimated adjusted risk ratios (aRRs) for preterm birth (<37 gestational weeks) and small-for-gestational age (SGA, <10th percentile weight for age)., Findings: Of infants to women with vs. without histological inflammation, 9.6% (n = 117) and 6.5% (n = 41) were preterm, respectively (aRR = 1.46; 95%CI = 1.03-2.06). Histological inflammation was associated with preterm birth in ulcerative colitis (UC) (aRR = 1.64; 95%CI = 1.07-2.52), especially extensive colitis (aRR = 2.37; 95%CI = 1.12-5.02), but not in Crohn's disease (aRR = 0.99; 95%CI = 0.55-1.78). Of infants to women with vs. without histological inflammation, 116 (9.6%) and 56 (8.9%), respectively, were SGA (aRR = 1.09; 95%CI = 0.81-1.47). Clinically active disease before pregnancy was linked to preterm birth (aRR = 1.42; 95%CI = 1.20-1.69), but not to SGA birth (aRR = 1.13; 95%CI = 0.96-1.32). Finally, of infants to women without clinical activity, histological inflammation was not significantly associated with preterm birth (aRR = 1.20; 95%CI = 0.68-2.13)., Interpretation: Histological and clinical activity in IBD, especially in UC, were risk factors for preterm birth. Further research is needed to determine the importance of pre-pregnancy histological activity in women without clinically-defined disease activity., Funding: The Swedish Society of Medicine., Competing Interests: Dr Ludvigsson has coordinated an unrelated study on behalf of the Swedish Quality Registry for IBD (SWIBREG). That study received funding from the Janssen corporation. Dr Olén has been PI for projects (unrelated to the current paper) at Karolinska Institutet financed by Janssen, Takeda, AbbVie, Ferring, and Pfizer grants. Karolinska Institutet has received fees for lectures (OO) and participation on advisory boards (OO) from Janssen, Ferring, Bristol Myers Squibb, Galapagos, and Takeda. Dr Halfvarson has served as a speaker or advisory board member for AbbVie, Celgene, Celltrion, Dr. Falk Pharma and the Falk Foundation, Ferring, Galapagos, Gilead, Hospira, Janssen, MEDA, Medivir, MSD, Novartis, Olink Proteomics, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, ThermoFisher Scientific, Tillotts Pharma, Vifor Pharma, and UCB. He has also received grant support from Janssen, MSD, and Takeda. Dr Axelrad has received research grants from BioFire Diagnostics; consultancy fees or honorarium from BioFire Diagnostics, Abbvie, Pfizer, and Janssen; and holds U.S. patent 2012/0052124A1. Dr. Bröms has participated in projects at Karolinska Institutet financed by grants from Janssen, Pfizer, and UCB. Lecturer for Takeda. Dr Marsal has served as a speaker, consultant, or advisory board member for AbbVie, Bayer, Bristol-Myers Squibb, Hospira, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, and Union Chimique Belge and has received grant support from AbbVie, Calpro AS, Fresenius Kabi, Pfizer, SVAR Life Science, and Takeda. The other authors report no conflicts of interest., (© 2022 The Author(s).)

Introduction: Inconsistent results have been reported on the association between folic acid use in pregnancy and risk of GDM. The aim of this study was to estimate the association between folic acid use and GDM in two population-based Nordic cohorts., Material and Methods: Two cohort studies were conducted using data from the national population registers in Norway (2005-2018, n = 791,709) and Sweden (2006-2016, n = 1,112,817). Logistic regression was used to estimate the associations between GDM and self-reported folic acid use and prescribed folic acid use, compared to non-users, adjusting for covariates. To quantify how potential unmeasured confounders may affect the estimates, E-values were reported. An exposure misclassification bias analysis was also performed., Results: In Norwegian and Swedish cohorts, adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for maternal self-reported folic acid use were 1.10 (1.06-1.14) and 0.89 (0.85-0.93), with E-values of 1.43 (1.31) and 1.50 (1.36), respectively. For prescribed folic acid use, ORs were 1.33 (1.15-1.53) and 1.56 (1.41-1.74), with E-values of 1.99 (1.57) and 2.49 (2.17), in Norway and Sweden respectively., Conclusions: The slightly higher or lower odds for GDM in self-reported users of folic acid in Norway and Sweden respectively, are likely not of clinical relevance and recommendations for folic acid use in pregnancy should remain unchanged. The two Nordic cohorts showed different directions of the association between self-reported folic acid use and GDM, but based on bias analysis, exposure misclassification is an unlikely explanation since there may still be differences in prevalence of use and residual confounding. Prescribed folic acid is used by women with specific comorbidities and co-medications, which likely underlies the higher odds for GDM., Competing Interests: CEC, GB, HK, IO, LP, SSC are or were employees at the time work on this study was performed at the Centre for Pharmacoepidemiology which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies, unrelated to this work. All other authors have no completing interest to declare.

Background: Population-level data spanning different countries describing oral and parenteral treatment in pregnant women with inflammatory bowel disease (IBD) are scarce. We studied treatment with sulfasalazine/5-aminosalicylates, corticosteroids, thiopurines/immunomodulators, and tumor necrosis factor (TNF)-inhibitors in the United States (Optum Clinformatics Data Mart and the Medicaid Analytics Extract [MAX]) and in the Swedish national health registers., Methods: We identified 2975 pregnant women in Optum (2004-2013), 3219 women in MAX (2001-2013), and 1713 women in Sweden (2006-2015) with a recorded diagnosis of IBD. We assessed patterns of use for each drug class according to filled prescriptions, assessing frequency of treatment continuation in those that were treated in the prepregnancy period., Results: The proportion of women with Crohn's disease and ulcerative colitis on any treatment during pregnancy was 56.1% and 56.3% in Optum, 47.5% and 49.3% in MAX, and 61.3% and 64.7% in Sweden, respectively, and remained stable over time. Sulfasalazine/5-aminosalicylates was the most commonly used treatment in Crohn's disease, ranging from 25.1% in MAX to 31.8% in Optum, and in ulcerative colitis, ranging from 34.9% in MAX to 53.6% in Sweden. From 2006 to 2012, the TNF-inhibitor use increased from 5.0% to 15.5% in Optum, from 3.6% to 8.5% in MAX, and from 0.7% to 8.3% in Sweden. Continuing TNF-inhibitor treatment throughout pregnancy was more common in Optum (55.8%) and in MAX (43.0%) than in Sweden (11.8%)., Conclusions: In this population-based study from 2 countries, the proportion of women with IBD treatment in pregnancy remained relatively constant. TNF-inhibitor use increased substantially in both countries., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: It is not known to what extent biologic treatment for IBD is captured in the Swedish Prescribed Drug Register (PDR) and the National Patient Register (NPR)., Methods: A cross-sectional study from July 2005 until 2017, comparing data on biologic treatment in the PDR and the NPR with medical records. We assessed the proportion of started treatment episodes in the medical records that were found in the PDR/NPR ever, within +/- one year and within +/- three months; for any biologic drug, per specific drug (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab), by calendar period (2005-2008, 2009-2012, and 2013-2017) and by study center. For adalimumab, we assessed the validity of end of treatment episodes., Results: Medical records of 1361 patients and 2323 treatment episodes with any biologic were reviewed and 80.1% (95% CI: 78.4-81.7) were ever captured in the PDR/NPR in. A time window of +/- one year or +/- three months reduced the sensitivity to 63.3% (95% CI: 61.3-65.3) and 52.6% (95% CI: 50.5-54.6), respectively. The sensitivity was high (>85%) for the prescribed injection drugs adalimumab, golimumab, and ustekinumab for all time windows and for adalimumab end of treatment, while considerably lower for the infusion drugs infliximab and vedolizumab., Conclusions: The PDR and the NPR are reliable data sources on treatment with injection biologics in patients with IBD in Sweden. Infliximab and vedolizumab are poorly captured, why PDR/NPR data should only be used after careful consideration of their limitations or complemented by other data sources, e.g., the disease-specific quality register SWIBREG.

Aims and Method: To assess whether the combination of motivational interviewing and psychoeducation affects relapse rate and stimulates involvement of people with psychosis in their treatment. We conducted an interventional study including patients with schizophrenia or schizoaffective disorder treated with oral antipsychotics, without previous experience of long-acting injectable antipsychotics (LAIs). They were randomised to either psychoeducation with motivational interviewing or a control group. Hospital admissions 18 months before and after the intervention, and switches to LAIs 18 months after the intervention, were recorded., Results: The two groups each comprised 101 participants. Fourteen from the intervention group and seven from the control group switched to LAIs. Five in the intervention group instigated the switch themselves, compared with zero controls (P = 0.06). Fourteen in the intervention group were readmitted to hospital during follow-up, compared with 23 in the control group (P = 0.14)., Clinical Implications: Psychoeducation with motivational interviewing may increase patients' involvement in their treatment and reduce the relapse frequency.

Background: Most anti-tumour necrosis factor (anti-TNF) agents are transferred across the placenta and may increase paediatric susceptibility to infections., Aims: To assess the risk of paediatric infections after maternal anti-TNF treatment., Methods: Population-based cohort study in Denmark, Finland and Sweden 2006-2013 in which 1027 children born to women with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis or inflammatory bowel disease, treated with anti-TNF, and 9346 children to women with non-biologic systemic treatment, were compared to 1 617 886 children of the general population. Children were followed for 3 years., Results: Adjusted by maternal age, parity, smoking, body mass index, country and calendar year, the incidence rate ratios with 95% confidence interval (CI) for hospital admissions for infection in the first year were 1.43 (1.23-1.67) for anti-TNF and 1.14 (1.07-1.21) for non-biologic systemic treatment, and 1.29 (1.11-1.50) and 1.09 (1.02-1.15), respectively, when additionally adjusting for adverse birth outcomes. There was a slight increase in antibiotic prescriptions in the second year for anti-TNF, 1.19 (1.11-1.29), and for non-biologic systemic treatment, 1.10 (1.07-1.13). There was no difference among anti-TNF agents, treatment in the third trimester, or between mono/combination therapy with non-biologic systemic treatment., Conclusions: Both anti-TNF and non-biologic systemic treatment were associated with an increased risk of paediatric infections. However, reassuringly, the increased risks were present regardless of treatment in the third trimester, or with combination treatment, and were not persistent during the first 3 years of life. Our findings may indicate a true risk, but could also be due to unadjusted confounding by disease severity and healthcare-seeking behaviour. This may in turn shift the risk-benefit equation towards continuation of treatment even in the third trimester., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Aim: To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents., Methods: Individually linked health data in Denmark (2000-2012), Finland (2005-2014), Iceland (2004-2017), Norway (2005-2015), Sweden (2006-2015), Germany (2006-2015), Australia (New South Wales, 2004-2012), Hong Kong (2001-2015), UK (2006-2016), and the US (Medicaid, 2000-2013, and IBM MarketScan, 2012-2015) were used. Using a uniformed approach, we estimated the prevalence of antipsychotic use as the proportion of pregnancies where a woman filled at least one antipsychotic prescription within three months before pregnancy until birth. For the Nordic countries, data were meta-analyzed to investigate maternal characteristics associated with the use of antipsychotics., Results: We included 8,394,343 pregnancies. Typical antipsychotic use was highest in the UK (4.4%) whereas atypical antipsychotic use was highest in the US Medicaid (1.5%). Atypical antipsychotic use increased over time in most populations, reaching 2% in Australia (2012) and US Medicaid (2013). In most countries, prochlorperazine was the most commonly used typical antipsychotic and quetiapine the most commonly used atypical antipsychotic. Use of antipsychotics decreased across the trimesters of pregnancy in all populations except Finland. Antipsychotic use was elevated among smokers and those with parity ≥4 in the Nordic countries., Conclusion: Antipsychotic use during pregnancy varied considerably between populations, partly explained by varying use of the typical antipsychotic prochlorperazine, which is often used for nausea and vomiting in early pregnancy. Increasing usage of atypical antipsychotics among pregnant women reflects the pattern that was previously reported for the general population., Competing Interests: Declaration of competing interest JR, CC, LP, and GB, are employees of the Centre for Pharmacopidemiology which receives funding from pharmaceutical companies and regulatory authorities for drug safety/utilization studies, unrelated to the submitted work. BTB has participated as an investigator on grants to the Brigham and Women's Hospital from Pfizer, GSK, Lilly, Baxalta, and Pacira, not related to the topic of the submitted work. SH-D has participated as investigator in projects funded by Pfizer, GSK, and Lilly; and consulted for Boehringer-Ingelheim, Roche and UCB as a methods advisor for pregnancy studies. KFH has participated as an investigator on grants to the Brigham and Women's Hospital from Boehringer Ingelheim, Pfizer, Lilly and GSK, not related to the topic of the submitted work. The other authors declare no personal conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To study the risk of preterm birth, caesarean section, and small for gestational age after anti-tumor necrosis factor agent treatment (anti-TNF) in pregnancy., Methods: Population-based study including women with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, and their infants born 2006 to 2013 from the national health registers in Denmark, Finland, and Sweden. Women treated with anti-TNF were compared with women with nonbiologic systemic treatment. Adalimumab, etanercept, and infliximab were compared pairwise. Continuation of treatment in early pregnancy was compared with discontinuation. Odds ratios with 95% confidence intervals were calculated in logistic regression models adjusted for country and maternal characteristics., Results: Among 1 633 909 births, 1027 infants were to women treated with anti-TNF and 9399 to women with nonbiologic systemic treatment. Compared with non-biologic systemic treatment, women with anti-TNF treatment had a higher risk of preterm birth, odds ratio 1.61 (1.29-2.02) and caesarean section, 1.57 (1.35-1.82). The odds ratio for small for gestational age was 1.36 (0.96-1.92). In pairwise comparisons, infliximab was associated with a higher risk of severely small for gestational age for inflammatory joint and skin diseases but not for inflammatory bowel disease. Discontinuation of anti-TNF had opposite effects on preterm birth for inflammatory bowel disease and inflammatory joint and skin diseases., Conclusions: Anti-TNF agents were associated with increased risks of preterm birth, caesarean section, and small for gestational age. However, the diverse findings across disease groups may indicate an association related to the underlying disease activity, rather than to agent-specific effects., (© 2020 John Wiley & Sons, Ltd.)

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., Competing Interests: Competing interests: CEC, GB, HK, LP, and IO are employees at the Centre for Pharmacoepidemiology, which receives grants from several entities (pharmaceutical companies, regulatory authorities and contract research organizations) for the performance of drug safety and drug utilization studies, unrelated to this work. HLG reports fees and grants from pharmaceutical companies in her previous position at Oslo University Hospital, unrelated to this work. SH-D reports receiving research grants to her institution from Eli Lilly, GlaxoSmithKline, and the National Institutes of Health and consulting fees from Roche unrelated to this work and having served as an epidemiologist with the North America AED pregnancy registry, which is funded by multiple companies. KFH reports receiving research grants to her institution from Eli Lilly, Pfizer, GlaxoSmithKline, and Boehringer-Ingelheim, unrelated to this work. BTB reports receiving grants to his institution from Eli Lilly, GlaxoSmithKline, Pacira, Baxalta, Pfizer, and Aetion unrelated to this work and having served on an expert panel for a postpartum hemorrhage quality improvement project that was conducted by the Association of Women’s Health, Obstetric, and Neonatal Nurses and funded by a grant from Merck for Mothers. All other authors have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Coeliac disease has been linked to anxiety and depression. However, their association with mucosal healing is unknown., Aim: To examine the relationship between anxiety, depression and mucosal healing in coeliac disease., Methods: Between 1969 and 2008, we collected data on all small intestinal biopsies with villous atrophy from Sweden's 28 pathology departments. We restricted our cohort to individuals with data on follow-up biopsy (either persistent villous atrophy [n = 3317] or mucosal healing [n = 4331]). Through Cox regression, we estimated hazard ratios (HRs) for anxiety or depression., Results: During follow-up, 123 (2.8/1000 person-years) individuals with mucosal healing had developed anxiety, compared to 94 (2.1/1000 person-years) with persistent villous atrophy. Mucosal healing was hence associated with a higher risk of future anxiety (HR = 1.49; 95% CI = 1.12-1.96). Similarly, 167 (3.8/1000 person-years) individuals with mucosal healing developed depression, compared to 148 (3.3/1000 person-years) with persistent villous atrophy, corresponding to a HR of 1.25 (95% CI = 0.99-1.59). Mucosal healing was more common in individuals with prior diagnoses of anxiety or depression before follow-up biopsy. Anxiety diagnosed between diagnostic and follow-up biopsy for coeliac disease was associated with an almost nine-fold increased chance of mucosal healing (odds ratio = 8.94; 95%CI = 2.03-39.27)., Conclusion: Anxiety and depression are more common in coeliac disease patients with mucosal healing, both before and after follow-up biopsy, an association potentially mediated through more vigilant compliance with a gluten-free diet. This finding raises concern that achieving the goal of mucosal healing may come at a cost of an increased risk of mood disorders., (© 2018 John Wiley & Sons Ltd.)

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.

Aims and method To assess the patients' most influential concerns regarding long-acting injectable antipsychotics (LAIs) and mental health professionals' preconceptions about these concerns. For both groups, to assess the level of knowledge about LAIs. This cross-sectional study used semi-structured interviews of patients with schizophrenia or schizoaffective disorder ( n = 164), nurses ( n = 43) and physicians ( n = 20). Results The mental health professionals overestimated many of the patients' fears of LAIs, and the expressed fears exceeded the actual experiences of patients already on LAIs. Acceptance to switch to LAIs was associated with shorter time from diagnosis. Nurses and patients disclosed limited knowledge of antipsychotics. Clinical implications Physicians and nurses should aim to identify the individual patient's concerns about LAIs in the discussion about choice of antipsychotic treatment early in the course of illness., Competing Interests: Declaration of interest L.Ö. has received speaker honoraria from Otsuka Pharma Scandinavia AB and H. Lundbeck AB, and has accepted travel and hospitality payment from Otsuka Pharma Scandinavia AB.

Background: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) have been associated with an increased risk of preterm birth., Material and Methods: We identified all 246 singleton preterm births among women with IBD between July 2006 and December 2010 as cases and an equal number of controls with IBD from the Swedish national health registers, matched by maternal age, parity and IBD diagnosis (CD/UC). From register data and medical charts, we obtained information on reproductive history, comorbidity, disease activity and drug treatment (corticosteroids, 5-aminosalicylates, sulfasalazine, thiopurines and anti-TNF) as risk factors for preterm birth. Associations were estimated using conditional logistic regression and results were presented as odds ratios (OR) with 95% confidence intervals (CI)., Results: Previous preterm birth was more common among cases, OR 6.13 (95%CI: 2.51-15.01). Significant activity at any time during pregnancy (OR: 2.20; 95%CI: 1.37-3.53), and in particular both in early and in late pregnancy, was more common for cases (OR: 4.78 95%; CI: 2.10-10.9). The OR for immunosuppressive treatment with thiopurines or anti-TNF was 1.88 (1.04-3.39) without significant activity and 12.78 (95%CI: 3.68-44.72) with. The risk for women who discontinued thiopurines was 6.56 (1.44-29.82)., Conclusions: Significant activity and immunosuppressive treatment was associated with preterm birth, particularly in women with both. The existing recommendations to aim at maintaining quiescent disease during pregnancy, even if it means continuing immunosuppressive treatment, are rational.

Background & Aims: Safety data on anti-tumor necrosis factor (anti-TNF) treatment during pregnancy are limited. We studied the risk of birth defects after anti-TNF treatment in early pregnancy., Methods: We collected data on 1,272,424 live-born infants identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. We determined the prevalence of birth defects among infants born to women with chronic inflammatory disease (inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or psoriasis), with (n = 683) and without (n = 21,549) anti-TNF treatment during early pregnancy, and in the general population. We compared the risk of any major birth defect and birth defect by organ system for infants born to women with chronic inflammatory disease, with and without anti-TNF treatment. Risks were presented as odds ratios (ORs) with 95% confidence intervals (CIs). We adjusted for maternal age, parity, smoking, body mass index, multiple gestation, country, and chronic inflammatory diagnosis., Results: Birth defects were more prevalent among infants born to women with chronic inflammatory disease, regardless of anti-TNF treatment status, than in the general population (4.8% vs 4.2%). Birth defects occurred in 43 of the infants born to the 683 women who received anti-TNF treatment (6.3%), and 1019 of the infants born to women with chronic inflammatory disease (4.7%). The OR for any defect in women receiving anti-TNF therapy was 1.32 (95% CI, 0.93-1.82); the OR for a cardiovascular defect was 1.60 (95% CI, 0.93-2.58), and the OR for a urinary defect was 2.22 (95% CI, 0.86-4.71)., Conclusions: Based on an analysis of data from the health registries in Denmark and Sweden, women who received anti-TNF agents during pregnancy had a slightly (but not significantly) higher risk of having children with birth defects. Although larger studies are needed, the heterogeneity of the observed birth defects did not indicate a common etiology., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Ulcerative colitis (UC) and Crohn's disease (CD) have been associated with increased risks of adverse birth outcomes. Disease activity and drug exposure may contribute to the association., Methods: A cohort from the Swedish health registers including 470,110 singleton births in Sweden from July 2006 to December 2010; 1833 to women with UC and 1220 to women with CD. Birth outcomes for women with UC and CD were compared with outcomes among those without disease. Diseased women were categorized by drug exposure, need of surgery, and hospital admissions as (1) no disease activity and (2) stable or (3) flaring disease. Logistic regression was used to calculate odds ratios with adjustments (aOR) for maternal age, parity, smoking status, body mass index, and comorbidity., Results: There were increased risks of preterm birth for both UC (aOR, 1.78; 95% confidence interval [CI], 1.49-2.13) and CD (aOR, 1.65; 95% CI, 1.33-2.06). Risks were more pronounced in women with flaring disease during pregnancy. Risks of small for gestational age, low Apgar score, and hypoglycemia were also increased. The risk of stillbirth was elevated in women with CD, particularly among those with flaring disease (aOR, 4.48; 95% CI, 1.67-11.90). Thiopurine exposure increased risks for preterm birth, both in women with stable (aOR, 2.41; 95% CI, 1.05-5.51) and with flaring disease (aOR, 4.90; 95% CI, 2.76-8.69)., Conclusions: Women with UC and CD are at increased risk of adverse birth outcomes, such as stillbirth, growth restriction, and preterm birth, particularly when they suffer from flares throughout pregnancy. Thiopurine exposure seems to further increase risks, independently of disease activity.

Background & Aims: Little is known about complications from ulcerative colitis (UC) or Crohn's disease (CD) during pregnancy and delivery. We assessed complications by using data from a large, population-based cohort., Methods: We analyzed data from 1209 women with UC, 787 women with CD, and 10,773 women without these diseases (the comparison group) by using the Medical Birth, Patient, and Prescribed Drug Registers of all residents in Sweden. All the women included in the analysis gave birth to a single infant between October 2006 and December 2009. We used data on medical treatment, surgery, and hospital admissions to assess disease activity. Risks of pregnancy and delivery complications were determined from adjusted odds ratios (aORs) with 95% confidence intervals (CIs)., Results: The risk of venous thromboembolism was increased among women with UC (aOR, 3.78; 95% CI, 1.52-9.38), particularly for those with flaring disease. Women with CD had a higher risk of antepartum hemorrhage (aOR, 1.66; 95% CI, 1.12-2.45), with the highest risks among those with no disease activity. Risks of elective cesarean delivery were more than doubled among women with UC (aOR, 2.44; 95% CI, 2.06-2.88) or CD (aOR, 2.31; 95% CI, 1.89-2.83). Women with UC (aOR, 1.39; 95% CI, 1.13-1.70) or CD (aOR, 1.50; 95% CI, 1.17-1.92) had increased risk for emergency cesarean delivery. Women with an inactive UC or flaring CD had the highest risks of cesarean delivery., Conclusions: Women with UC or CD have more complications during pregnancy and delivery than women without these diseases. Disease activity affects mode of delivery, and thrombophilic events present differently in women with UC vs CD., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)