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Leon Alexander Mclaren Berge, 1, 2 Bettina Kulle Andreassen, 1 Jo S Stenehjem, 1–3 Trond Heir, 4, 5 Kari Furu, 6 Asta Juzeniene, 7 Ingrid Roscher, 8 Inger Kristin Larsen, 9 Adele C Green, 10, 11 Marit B Veierød, 2 Trude E Robsahm 1 1Department of Research, Cancer Registry of Norway, Oslo, Norway; 2Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; 3Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway; 4Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; 5Oslo Ischemia Study, Oslo University Hospital, Oslo, Norway; 6Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway; 7Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; 8Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital, Oslo, Norway; 9Department of Registration, Cancer Registry of Norway, Oslo, Norway; 10QIMR Berghofer Medical Research Institute, Brisbane, Australia; 11CRUK Manchester Institute, University of Manchester, Manchester, UKCorrespondence: Leon Alexander Mclaren BergeCancer Registry of Norway, P.O. Box 5313 Majorstuen, Oslo N-0304, NorwayTel +47 99605034Email Leon.Berge@kreftregisteret.noPurpose: Melanoma is the cancer with the most rapidly rising incidence rate in Norway. Although exposure to ultraviolet radiation (UVR) is the major environmental risk factor, other factors may also contribute. Antidepressants have cancer inhibiting and promoting side effects, and their prescription rates have increased in parallel with melanoma incidence. Thus, we aimed to prospectively examine the association between use of antidepressants and melanoma by using nation-wide data from the Cancer Registry of Norway, the National Registry, the Norwegian Prescription Database and the Medical Birth Registry of Norway.Patient and Methods: All cases aged 18– 85 with a primary cutaneous invasive melanoma diagnosed during 2007– 2015 (n=12,099) were matched to population controls 1:10 (n=118,467) by sex and year of birth using risk-set sampling. We obtained information on prescribed antidepressants and other potentially confounding drug use (2004– 2015). Conditional logistic regression was used to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) for the association between overall and class-specific use of antidepressants and incident melanoma.Results: Compared with ≤ 1 prescription, ≥ 8 prescriptions of antidepressants overall were negatively associated with melanoma (RR 0.81 CI 0.75– 0.87). Class-specific analyses showed decreased RRs for selective serotonin reuptake inhibitors (RR 0.82 CI 0.73– 0.93) and mixed antidepressants (RR 0.77 CI 0.69– 0.86). The negative association was found for both sexes, age ≥ 50 years, residential regions with medium and highest ambient UVR exposure, all histological subtypes, trunk, upper and lower limb sites and local disease.Conclusion: Use of antidepressants was associated with decreased risk of melanoma. There are at least two possible explanations for our results; cancer-inhibiting actions induced by the drug and less UVR exposure among the most frequent users of antidepressants.Keywords: antidepressants, melanoma, prescription drugs, pharmacoepidemiology, registry-based

Objective: To compare antidepressant utilization in individuals aged 5–19 years from the Scandinavian countries. Methods: A population‐based drug utilization study using publicly available data of antidepressant use from Denmark, Norway, and Sweden. Results: In the study period from 2007 to 2017, the proportion of antidepressant users increased markedly in Sweden (9.3–18.0/1000) compared to Norway (5.1–7.6/1000) and Denmark (9.3–7.5/1000). In 2017, the cumulated defined daily doses (DDD) of selective serotonin reuptake inhibitors were 5611/1000 inhabitants in Sweden, 2709/1000 in Denmark, and 1848/1000 in Norway. The use of 'other antidepressants' (ATC code N06AX) also increased in Sweden with a higher DDD in 2017 (497/1000) compared to Denmark (225/1000) and Norway (170/1000). The use of tricyclic antidepressants was generally low in 2017 with DDDs ranging between 30–42 per 1000. The proportion of antidepressant users was highest among 15‐ to 19‐year‐old individuals. Girls were more likely to receive treatment than boys, and the treated female/male ratios per 1000 were similar in Sweden (2.39), Denmark (2.44), and Norway (2.63). Conclusion: Even in highly comparable healthcare systems like the Scandinavian countries', variation in antidepressant use is considerable. Swedish children and adolescents have a markedly higher and still increasing use of antidepressants compared to Danish and Norwegian peers. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the association between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and motor development in children considering the effect of maternal symptoms of anxiety and depression before, during and after pregnancy.Design: Population-based prospective pregnancy cohort study.Setting: The Norwegian Mother and Child Cohort study (MoBa) (1999-2008).Population: A total of 51 404 singleton pregnancies.Methods: Self-reported use of SSRIs was collected for the 6 months before pregnancy and prospectively during pregnancy. We used ordinal logistic regression as the statistical analysis.Main Outcome Measures: Motor development was assessed by maternal reports of fine and gross motor development at child age 3 years by items from the Ages and Stages Questionnaire (ASQ). The maternal ASQ scores were compared with data from a MoBa sub-study where clinicians assessed motor development with the Gross and Fine Motor Mullen scales of early learning.Results: In all 381 women (0.7%) reported use of SSRIs during pregnancy, of these 159 reported on at least two questionnaires (prolonged use). Prolonged SSRI exposure was associated with a delay in fine motor development, odds ratio 1.42 (95% CI 1.07-1.87) compared with no SSRI exposure, after adjusting for symptoms of anxiety and depression before and during pregnancy. Severity of maternal depression seemed to explain the association only partially. Stratifying on depression after pregnancy had no impact on the estimated effect of SSRIs.Conclusions: Prolonged prenatal exposure to SSRIs was weakly associated with a delayed motor development at age 3 years, but not to the extent that the delay was of clinical importance.Tweetable Abstract: Long-term prenatal SSRI exposure is weakly associated with delayed motor development independent of depression. [ABSTRACT FROM AUTHOR]

Objectives: To explore the association between antidepressant use during pregnancy and birth outcomes., Design: Cohort study., Setting: Electronic health record data., Participants: 2 528 916 singleton births from the UK's Clinical Practice Research Datalink (1996-2018), Norway's Medical Birth Registry (2009-2020), and Sweden's Medical Birth Register (2006-2020)., Main Outcome Measures: Stillbirth, neonatal death, pre- and post-term delivery, small and large for gestational age, and low Apgar score five minutes post-delivery., Results: A total of 120 209 (4.8%) deliveries were exposed to maternal antidepressant use during pregnancy. Maternal antidepressant use during pregnancy was associated with increased odds of stillbirth (adjusted pooled OR (aOR) 1.16, 95% CI 1.05 to 1.28), preterm delivery (aOR 1.26, 95% CI 1.23 to 1.30), and Apgar score < 7 at 5 minutes (aOR 1.83, 95% CI 1.75 to 1.91). These findings persisted in the discordant sibling analysis, but with higher uncertainty. The adjusted predicted absolute risk for stillbirth was 0.34% (95% CI 0.33 to 0.35) among the unexposed and 0.40% (95% CI 0.36 to 0.44) in the antidepressant exposed. Restricting to women with depression or anxiety, the association between antidepressant exposure and stillbirth attenuated (aOR 1.07, 95% CI 0.94 to 1.21). Paternal antidepressant use was modestly associated with preterm delivery and low Apgar score. Most antidepressants were associated with preterm delivery (except paroxetine) and Apgar score (except mirtazapine and amitriptyline)., Conclusions: Maternal antidepressant use during pregnancy may increase the risk of stillbirth, preterm delivery, and low Apgar score, although the absolute risks remained low. Confounding by severity of indication cannot be ruled out, as the severity of symptoms was not available. The modest association between paternal antidepressant use and both preterm delivery and low Apgar score suggests that residual confounding by familial environment cannot be ruled out.

Importance: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are consistently reported to be discontinued by approximately half of pregnant women. Little is known about how this may be associated with postpartum psychiatric health., Objective: To investigate associations of SSRI or SNRI discontinuation in pregnant women with depression or anxiety and psychiatric health and sick leave absence after childbirth., Design, Setting, and Participants: This population-based cohort study was conducted between 2006 and 2019 using data from Swedish population-based registers. Pregnant women with a filled prescription of an SSRI or SNRI in the 90 days before pregnancy without recorded comorbid or severe psychiatric conditions were included. Analyses were performed in November 2023., Exposures: K-means for longitudinal data was used to cluster trajectories of SSRI and SNRI use during pregnancy, resulting in 2 trajectory groups based on the number of days covered, defined as continued and discontinued use groups., Main Outcomes and Measures: The primary outcome was psychiatric-related hospitalizations by 90 days after childbirth. Secondary outcomes included psychiatric-related outpatient visits, self-harm and suicide, and any-cause mortality by 90 days after childbirth and all outcomes plus sick leave absence by 1.5 years after childbirth., Results: Among 27 773 pregnant women (17 241 aged ≥30 years [62.1%] at childbirth), 13 184 women (47.5%) had discontinued SSRI or SNRI use and 14 589 individuals (52.5%) had continued use. Individuals in the discontinued compared with continued use group were younger (5588 women [42.4%] vs 4944 women [33.9%] aged <30 years), less educated (4281 women [32.5%] vs 5821 women [39.9%] who completed postsecondary education or above), and more likely to have smoked in early pregnancy (1445 individuals [11.0%] vs 1180 individuals [8.1%]), been born in a non-Nordic country (1641 individuals [12.4%] vs 975 individuals [6.7%]), and used anxiolytics (1301 individuals [9.9%] vs 1119 individuals [7.7%]) and hypnotics and sedatives (1609 individuals [12.2%] vs 1510 individuals [10.4%]). Psychiatric-related hospitalizations occurred in 49 individuals (0.4%) in the discontinued vs 59 individuals (0.5%) in the continued use group in the 90 days after childbirth, with an adjusted hazard ratio (aHR) of 1.28 (95% CI, 0.85-1.91), while at 1.5 years after childbirth, the aHR was 0.81 (95% CI, 0.66-1.00). Lower hazard rates for psychiatric-related outpatient visits in the discontinued vs continued use group at 90 days (aHR, 0.59; 95% CI, 0.53-0.66) and 1.5 years (aHR, 0.60; 95% CI, 0.57-0.64) after childbirth were found. No difference in sick leave absence was found; however, individuals who discontinued had fewer days of sick leave by 1.5 years after childbirth than those who continued (mean [SD], 44.6 [70.6] days vs 53.1 [82.3] days)., Conclusions and Relevance: In this study, approximately half of pregnant women discontinued SSRIs or SNRIs, and discontinuation during pregnancy was not associated with adverse psychiatric-related outcomes, including hospitalizations, outpatient visits, suicidal behavior, or sick leave absence in the 90 days or 1.5 years after childbirth.

Objective: Little is known about thyroid cancer survivors' risk of chronic conditions. We, therefore, investigated the prevalence of drugs used for chronic conditions among thyroid cancer patients using population-wide register data., Methods: We linked data from the Cancer Registry of Norway to the Norwegian Prescription Database and other databases for a study population of 3.52 million individuals, including 3486 individuals with thyroid cancer diagnosed during 2005-2019. Prevalence ratios (PRs) with 95% CIs of reimbursed prescribed drugs in thyroid cancer patients up to 15 years after thyroid cancer diagnosis were estimated by log-binomial regression, with the cancer-free population as reference., Results: Individuals (both males and females) with thyroid cancer had higher use of drugs for several chronic conditions in the years after diagnosis; eg, 5 years after thyroid cancer diagnosis, there was elevated use of drugs for hypoparathyroidism (PRmales = 35.4, 95% CI, 25.2-49.7; PRfemales = 42.8, 95% CI, 34.2-53.6), hypertension (PRfemales = 1.20, 95% CI, 1.12-1.28), anxiety and tension (PRmales = 4.01, 95% CI, 1.80-8.92; PRfemales = 2.01, 95% CI, 1.15-3.52), gastric acid disorders (PRmales = 1.52, 95% CI, 1.22-1.91; PRfemales = 1.45, 95% CI, 1.27-1.66), and pain (PRmales = 1.48, 95% CI, 1.11-1.97; PRfemales = 1.24, 95% CI, 1.08-1.42) as compared with the cancer-free population. In addition, males with thyroid cancer had long-term elevated use of drugs for depression (eg, year 10+, PRmales = 1.66, 95% CI, 1.06-2.59). Individuals with thyroid cancer also had higher use of drugs for several conditions prior to the thyroid cancer diagnosis, eg, hypertension, gastric acid disorders, and pain., Conclusions: Individuals diagnosed with thyroid cancer had elevated long-term use of drugs for several chronic conditions, as compared with the cancer-free population., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Importance: Significant evidence gaps exist regarding the safety of smoking cessation pharmacotherapies during pregnancy, especially for the risk of congenital malformations. Consequently, professional bodies advise against the use of varenicline and bupropion and recommend caution with nicotine replacement therapy (NRT). Contemporary estimates of the use of smoking cessation pharmacotherapies during pregnancy are lacking., Objective: To quantify the proportion of individuals using prescribed smoking cessation pharmacotherapies during pregnancy and during the first trimester specifically, in 4 countries., Design, Setting, and Participants: This retrospective, population-based cohort study used linked birth records, hospital admission records, and dispensing records of prescribed medications from all pregnancies resulting in birth between 2015 and 2020 in New South Wales, Australia; New Zealand; Norway; and Sweden. Data analyses were conducted in October and November 2023., Exposure: Prescribed smoking cessation pharmacotherapy use (varenicline, NRT, and bupropion) during pregnancy was defined as days' supply overlapping the period from date of conception to childbirth., Main Outcomes and Measures: Prevalence of use among all pregnancies and pregnancies with maternal smoking were calculated. Among women who used a pharmacotherapy, the proportion of women with use during the first trimester of pregnancy was also calculated., Results: Among 1 700 638 pregnancies in 4 countries, 138 033 (8.1%) had maternal smoking and 729 498 (42.9%) were younger than 30 years. The prevalences ranged from 0.02% to 0.14% for varenicline, less than 0.01% to 1.86% for prescribed NRT, and less than 0.01% to 0.07% for bupropion. Among pregnant individuals who smoked, use of pharmacotherapies was up to 10 times higher, with maximum prevalences of 1.25% for varenicline in New South Wales, 11.39% for NRT in New Zealand, and 0.39% for bupropion in New Zealand. Use in the first trimester occurred among more than 90% of individuals using varenicline, approximately 60% among those using NRT, and 80% to 90% among those using bupropion., Conclusions and Relevance: In this cohort study of pregnant individuals in 4 high-income countries, the low prevalence of varenicline and bupropion use during pregnancy and higher prevalence of NRT use aligned with current clinical guidelines. As most use occurred in the first trimester, there is a need for evidence on the risk of congenital malformations for these medications.

Aims: To describe trends in the use of anti-obesity drugs in Norway during the period 2004-2022., Materials and Methods: We assessed the annual utilization of any available drug indicated for obesity recorded in the nationwide Norwegian Prescribed Drug Register for adults (age 18-79 years) from 1 January 2004 to 31 December 2022. Prevalence was stratified by sex and age group (18-29 years and 10-year age groups thereafter). Additional analyses were performed in individuals initiating treatment with an anti-obesity drug and on the cost of the anti-obesity drugs since 2017., Results: The prevalence of anti-obesity drug use decreased from 2009, when sibutramine and rimonabant were withdrawn from the market, and increased again after the approval of bupropion-naltrexone in 2017 and liraglutide in 2018. The use of the peripheral-acting anti-obesity drug orlistat decreased from 2004. In 2022, 1.04% of the adult Norwegian population (72.8% women) filled at least one prescription of bupropion-naltrexone, 0.91% used liraglutide (Saxenda; 74.2% women), and semaglutide without reimbursement was used by 0.68% (76.7% women). The prevalence increased with age, peaking in the age group 50 to 59 years, and decreased in older age groups. From 2017 to 2022, 2.8% of the adult residents initiated treatment with an anti-obesity drug. The total sale of those drugs increased from 1.1 million euros in 2017 to 91.8 million euros in 2022., Conclusions: The use of anti-obesity drugs in Norway has increased substantially in recent years, especially among women aged 40 to 59 years. Changes in availability and reimbursement have influenced the use of these drugs in recent years., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The aim of this study was to examine variations in use of antidepressants among children and adolescents in the three Scandinavian countries (Sweden, Norway, and Denmark). We identified new users of antidepressants (5-17 years) during 2007-2018 and described the annual incidence rate, treatment duration, concomitant psychotropic drug use, and the clinical setting of the prescribing physician (in Sweden and Denmark). Incident use of antidepressants increased by a factor 1.9 in Sweden, 1.3 in Norway and decreased by a factor 0.6 in Denmark during the study period. In Sweden, 58% of antidepressant users were covered by a prescription 12 months after initiation compared to 40% in Norway and 49% in Denmark. Also, 34% of Swedish antidepressant users were in continuous treatment after 12 months compared to 26% in Norway and 31% in Denmark. Concomitant use of other psychotropics was more common in Sweden (57%) than in Norway (37%) and Denmark (27%). During 2007-2018, clinicians from psychiatry settings initiated 75% of antidepressant treatments in Sweden, while this was the case for 50% of prescriptions in Denmark, although the proportion increased over time. The number of new antidepressant users is high and still rising in Sweden compared to Norway and Denmark. Swedish antidepressant users are more likely to use other psychotropics and to be covered by an antidepressant prescription after one year. Most antidepressants in Sweden are prescribed by physicians within psychiatric settings suggesting that they are based on specialized psychiatric evaluation., (© 2024. The Author(s).)

Background: Antipsychotics are commonly prescribed to treat a range of psychiatric conditions in women of reproductive age and during pregnancy, including schizophrenia, bipolar disorder, anxiety, depression, autism spectrum disorder, and insomnia. This study aimed to evaluate whether children exposed to antipsychotic medication prenatally are at increased risk of specific neurodevelopmental disorders and learning difficulties., Methods: Our population-based cohort study used nationwide register data (1 January 2000-31 December 2020) on pregnant women diagnosed with a psychiatric disorder and their live-born singletons from Denmark, Finland, Iceland, Norway, and Sweden. Cox proportional hazard regression yielded propensity score-weighted hazard ratios (aHRs) and 95% confidence intervals (CIs) for risk of intellectual-, speech or language-, learning-developmental disorders, and a composite outcome of the listed disorders. We defined poor performance as scoring within the lowest quartile on national school tests in mathematics and language arts. We estimated propensity score-weighted risk ratios (aRRs) using Poisson regression. We analysed data from Denmark separately and pooled results using random effects meta-analysis., Findings: Among 213,302 children (median follow-up: 6.7 years), 11 626 (5.5%) were exposed to antipsychotics prenatally. Adjusted risk estimates did not suggest an increased risk of neurodevelopmental disorders: aHR of 1.06 (95% CI 0.94-1.20) for the composite outcome, or for poor academic performance: aRR of 1.04 (95% CI 0.91-1.18) in mathematics, and of 1.00 (95% CI 0.87-1.15) in language arts. Results were generally consistent across individual medications, trimesters of exposure, sibling- and sensitivity analyses., Interpretation: The findings of this large multinational cohort study suggest there is little to no increased risk of child neurodevelopmental disorders or learning difficulties after prenatal exposure to antipsychotics. Our findings can assist clinicians and women managing mental illness during pregnancy., Funding: This study was funded by the NordForsk Nordic Program on Health and Welfare (Nordic Pregnancy Drug Safety Studies, project No. 83539), by the Research Council of Norway (International Pregnancy Drug Safety Studies, project No. 273366) and by the Research Council of Norway through its Centres of Excellence funding scheme (project No. 262700), and UNSW Scientia Programme Awards (PS46019, PS46019-A)., Competing Interests: CEC and JR are employees of the Centre for Pharmacoepidemiology at Karolinska Institutet, which receives funding from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies, unrelated to this work. KF, ØK, and VH report participation in regulator mandated phase IV studies (PASS) unrelated to the submitted work, funded by pharmaceutical companies (Novo Nordisk, LEO Pharma and Bristol Myers Squibb) and paid to the institution (no personal fees). MG and MKL Leinonen report a grant from the Innovative Medicines Initiative (IMI ConcePTION, grant agreement number 821520) while conducting the study, unrelated to this work. MG and MKL also report that their institution has received funding from pharmaceutical companies to conduct regulator mandated post-marketing drug safety research outside the submitted work. MHB reported fees paid to her institution by valproate market authorization holders for EMA-mandated contract research (PASS studies); speaking and/or consultancy honoraria from Eisai, Novartis Norway, Jazz Pharmaceuticals, Angelini Pharma, AbbVie, Teva, Lilly, and Lundbeck unrelated to the medications in the study. All other authors do not report any competing interests., (© 2024 The Authors.)

Low birth weight raises neonatal risks and lifelong health issues and is linked to maternal medication use during pregnancy. We examined data from the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, including 69,828 offspring with genotype data and 81,189 with maternal genotype data. We identified genetic risk variants in placental efflux transporters, calculated genetic scores based on alleles related to transporter activity, and assessed their interaction with prenatal use of antiseizure or antidepressant medication on offspring birth weight. Our study uncovered possible genetic variants in both offspring (rs3740066) and mothers (rs10248420; rs2235015) in placental efflux transporters (MRP2- ABCC2 and MDR1- ABCB1 ) that modulated the association between prenatal exposure to antiseizure medication and low birth weight in the offspring. Antidepressant exposure was associated with low birth weight, but there were no gene-drug interactions. The interplay between MRP2- ABCC2 and MDR1- ABCB1 variants and antiseizure medication may impact neonatal birth weight., Competing Interests: O.A.A. is a consultant for cortechs.ai and has received speaker’s honorarium from Janssen, Lundbeck, and Sunovion unrelated to the current work. The rest of the authors declare that no competing interests exist., (© 2024 The Author(s).)

Importance: Increasing use of second-line noninsulin antidiabetic medication (ADM) in pregnant individuals with type 2 diabetes (T2D) may result in fetal exposure, but their teratogenic risk is unknown., Objective: To evaluate periconceptional use of second-line noninsulin ADMs and whether it is associated with increased risk of major congenital malformations (MCMs) in the infant., Design, Setting, and Participants: This observational population-based cohort study used data from 4 Nordic countries (2009-2020), the US MarketScan Database (2012-2021), and the Israeli Maccabi Health Services database (2009-2020). Pregnant women with T2D were identified and their live-born infants were followed until up to 1 year after birth., Exposure: Periconceptional exposure was defined as 1 or more prescription fill of sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, or insulin (active comparator) from 90 days before pregnancy to end of first trimester., Main Outcomes and Measures: Relative risks (RRs) and 95% CIs for MCMs were estimated using log-binomial regression models, adjusting for key confounders in each cohort and meta-analyzed., Results: Periconceptional exposure to second-line noninsulin ADMs differed between countries (32, 295, and 73 per 100 000 pregnancies in the Nordics, US, and Israel, respectively), and increased over the study period, especially in the US. The standardized prevalence of MCMs was 3.7% in all infants (n = 3 514 865), 5.3% in the infants born to women with T2D (n = 51 826), and among infants exposed to sulfonylureas was 9.7% (n = 1362); DPP-4 inhibitors, 6.1% (n = 687); GLP-1 receptor agonists, 8.3% (n = 938); SGLT2 inhibitors, 7.0% (n = 335); and insulin, 7.8% (n = 5078). Compared with insulin, adjusted RRs for MCMs were 1.18 (95% CI, 0.94-1.48), 0.83 (95% CI, 0.64-1.06), 0.95 (95% CI, 0.72-1.26), and 0.98 (95% CI, 0.65-1.46) for infants exposed to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, respectively., Conclusions and Relevance: Use of second-line noninsulin ADMs is rapidly increasing for treatment of T2D and other indications, resulting in an increasing number of exposed pregnancies. Although some estimates were imprecise, results did not indicate a large increased risk of MCMs above the risk conferred by maternal T2D requiring second-line treatment. Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise estimates as data accumulate.

Background and Objectives: Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy., Methods: We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis., Results: Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses., Discussion: Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined., Classification of Evidence: This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

Aims: Estimate prevalence of gestational diabetes mellitus (GDM) and its treatment in Norway 2010-2020 and explore impact of new national GDM guidelines in 2017., Methods: We identified women giving birth in a nationwide cohort study using registers on births, prescriptions, education, primary and specialist care. For each year, we estimated prevalence of GDM overall, by BMI, age, education, and mother's birthplace; proportions of GDM pregnancies receiving pharmacological treatment; and distribution of the gestational week when GDM was diagnosed., Results: In 633,169 pregnancies, prevalence of GDM increased from 2.6 % in 2010 to 6.0 % in 2016, then stabilized. Similar patterns were seen across strata of BMI, age, education, and maternal birthplace, although prevalence was higher with higher BMI, higher age, lower education, and mothers born in Asia, Africa, or Middle East. The proportion of the GDM population pharmacologically treated increased from 11.6 % in 2010 to 13.6 % in 2016 and 31.6 % in 2020. GDM was diagnosed in recommended gestational week 24-28 in 19 % versus 45 % of GDM pregnancies in 2010 and 2020, respectively., Conclusions: Both the proportion diagnosed with GDM within recommended time of screening, and who received pharmacological treatment, increased substantially following new guidelines in 2017. Prevalence of GDM increased from 2010 to 2016, then plateaued., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [KF, ØK, PLDR and VH report participation in research projects funded by pharmaceutical companies (one on diabetes drug), all regulator mandated post-authorisation safety studies (PASS) unrelated to the submitted work, all with funds paid to the institution (no personal fees). KAW, LJK and HLG report no conflicts of interest.]., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To describe ADHD medication use trajectories around pregnancy in Norway and Sweden., Methods: We identified pregnancies resulting in births using linked data from birth and prescribed drug registers of Norway (2006-2019, N = 813 107) and Sweden (2007-2018, N = 1 269 146). We restricted to women who filled prescriptions for ADHD medication during pregnancy or in the year before or after. We described exposure as use versus no use, and total amount of drug dispensed in defined daily doses (DDDs). Group-based trajectory modeling was used to identify distinct medication use trajectories., Results: In total, 13 286 women (0.64%) filled a prescription for ADHD medication. We identified four trajectory groups: continuers (5.7%), interrupters (23.8%), discontinuers (49.5%), and late initiators (21.0%). Discontinuers were younger, continuers were older on average. More women continued medication in recent years (2014-2019). Most discontinuers (60.7%) were nulliparous; more initiators and continuers had one or multiple previous births, respectively. Continuers were least likely to live with a partner (65.8%). Discontinuers were least likely (24.7%) and continuers most likely (37.6%) to smoke at the beginning of pregnancy. More continuers used amphetamine derivatives and were most likely to use other psychotropics. On modeling continuers, we identified three dose-trajectory groups which suggested that most women reduced medication dose during pregnancy., Conclusions: Most pregnant women discontinued or interrupted their ADHD medication during pregnancy, but more continued in recent years. Continuers were more likely to have had previous births, less likely to have lived with a partner, and may have had additional comorbidities warranting the use of other psychotropics., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

The objective of the study was to compare the use of attention deficit hyperactivity disorder (ADHD) medication among children and adolescents in Scandinavia 2010-2020. Using aggregated prescription data for individuals aged 5-19 years, we calculated annual prevalence proportions of ADHD medication (users/1000 inhabitants) for each country, overall and stratified by age and sex. Overall, use of ADHD medication increased during 2010-2020 in all countries. The increase was pronounced in Sweden reaching 35 users/1000 inhabitants in 2020 (119% increase), whereas it reached 22/1000 in Denmark and Norway (equivalent to a 38% and 16% increase, respectively). Methylphenidate was the most frequently used drug and Sweden had the highest use reaching 25/1000 in 2020 compared to 16/1000 and 18/1000 in Denmark and Norway, respectively. Lisdexamfetamine use increased steadily and was also highest in Sweden (13/1000 in 2020). In 2020, atomoxetine use was higher in Sweden (4.6/1000) and Denmark (4.5/1000) compared to Norway (2.2/1000). From 2015, use of guanfacine increased in Sweden reaching 4.4/1000 in 2020 but remained low in Denmark (0.4/1000) and Norway (0.7/1000). Use of dexamphetamine was low (ranging from 0.47 to 0.75/1000 in 2020) in the three countries. ADHD medication use was highest in Sweden across all age groups. In all countries, the prevalence was higher in males compared to females. In conclusion, use of ADHD medication among children and adolescents in Scandinavia is increasing. The prevalence of use is higher in Sweden for all drug groups compared to Norway and Denmark., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: To assess the risk of major congenital malformations with metformin versus insulin in pregnancies with type 2 diabetes., Research Design and Methods: This cohort study used four Nordic countries' nationwide registers of live and stillborn infants exposed to metformin or insulin during first trimester organogenesis. Main exclusion criteria were type 1 diabetes, polycystic ovary syndrome, fertility treatment, and exposure to other diabetes drugs. Adjusted risk ratios (RRs) and 95% CIs were estimated for any and cardiac malformations., Results: Of 3,734,125 infants in the source population, 25,956 were exposed to metformin or insulin in the first trimester, and 4,023 singleton infants were included. A malformation was diagnosed in 147 (4.7%) of 3,145 infants with exposure to any metformin (alone or in addition to insulin) and 50 (5.7%) of 878 infants with exposure to insulin alone (RR 0.84, 95% CI 0.46-1.54). Among 2,852 infants exposed to metformin alone and 293 infants exposed to metformin in addition to insulin 127 (4.4%) and 20 (6.8%), respectively, had a malformation. The adjusted risk was not increased for either metformin alone (0.83, 0.44-1.58) or both metformin and insulin (0.98, 0.56-1.69) versus insulin alone. Corresponding RRs for cardiac malformations were 1.01 (0.55-1.84) for any metformin, 0.92 (0.47-1.81) for metformin alone, and 1.72 (0.76-3.91) for both metformin and insulin., Conclusions: No evidence of an increased malformation risk with metformin versus insulin in the first trimester was found. Results should be interpreted with caution since information on glycemic control was missing., (© 2023 by the American Diabetes Association.)

Importance: Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied., Objective: To examine the association between prenatal exposure to ASM with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy., Design, Setting, and Participants: This prospective, population-based register study assessed 4 546 605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4 546 605 children, 54 953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38 661 children of mothers with epilepsy were identified. Data analysis was performed from August 2021 to January 2023., Exposures: Prenatal exposure to ASM was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth., Main Outcomes and Measures: The main outcome measure was diagnosis of psychiatric disorders (a combined end point and 13 individual disorders). Estimated adjusted hazard ratios (aHRs) using Cox proportional hazards regression and cumulative incidences with 95% CIs are reported., Results: Among the 38 661 children of mothers with epilepsy (16 458 [42.6%] exposed to ASM; 19 582 [51.3%] male; mean [SD] age at the end of study, 7.5 [4.6] years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 [95% CI, 1.60-2.03]; cumulative risk at 18 years in ASM-exposed children, 42.1% [95% CI, 38.2%-45.8%]; cumulative risk at 18 years in unexposed children, 31.3% [95% CI, 28.9%-33.6%]), which was driven mainly by disorders within the neurodevelopmental spectrum. Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, whereas associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and attention-deficit/hyperactivity disorder (aHR, 1.78; 95% CI, 1.03-3.07)., Conclusions and Relevance: Findings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam. This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.

Objectives: To evaluate both incidence and prevalence of drugs used for chronic diseases in survivors of adult-onset gynaecological cancer., Design: A prospective study., Setting: Population-based registries., Population: 1.76 million women, including 17 500 women with gynaecological cancers., Methods: Data from the Cancer Registry of Norway was linked to the Norwegian Prescription Database and other national databases., Main Outcome Measures: Prevalence ratios (PRs) and hazard ratios (HRs), with 95% confidence intervals (CIs), of dispensed drugs in gynaecological cancer patients (up to 15 years after diagnosis) were estimated by log-binomial and Cox regression, respectively, with cancer-free women as reference., Results: For gynaecological cancer patients, the incidence of drugs used for pain control was higher than in cancer-free women, especially the first 5 years after diagnosis, and the prevalence was high at least 10 years after. The prevalence of sex hormones was high in women with gynaecological cancer at least 10 years after diagnosis (cervical and ovarian cancer PR = 23, 95% CI 18-30 and PR = 29, 95% CI 15-38, respectively), but low in cancer-free women (0.3%). Patients with uterine corpus cancer had a higher prevalence of antidiabetics before and at least 10 years after diagnosis, most pronounced in women diagnosed before age 50 (PR = 10, 95% CI 5.0-21). The prevalence of antidepressants was moderately elevated in women with gynaecological cancers., Conclusions: Gynaecological cancer survivors, particularly cervical and ovarian cancer survivors, had an increased long-term use of drugs for pain control and sex hormones. Survivors of uterine corpus cancer used antidiabetics more often, both before and after diagnosis., (© 2023 John Wiley & Sons Ltd.)

Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype., Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights., Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not., Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections., Methods and Analysis: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed., Ethics and Dissemination: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals., Trial Registration Number: EUPAS30280., Competing Interests: Competing interests: MR and PBJ report participation in research funded by LEO Pharma A/S (no personal fees). participation in studies funded by Alcon, Almirall, Astellas, AstraZeneca, Boehringer-Ingelheim, Novo Nordisk, Servier, Pfizer, Menarini Pharmaceuticals, and LEO Pharma, all regulator mandated phase IV studies, all with funds paid to the institution (no personal fees). JH has received teaching fees from Atrium. HS reports participation in research funded by LEO Pharma A/S (no personal fees). He has received personal consulting fees from Bristol-Myers-Squibb, Novartis, Roche, Merck and Pfizer outside the submitted work. He has received teaching fees from Atrium. KF and ØK reports participation in research projects funded by Novo Nordisk and LEO Pharma, all regulator mandated phase IV studies, all with funds paid to the institution (no personal fees). ES, EH and RH are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. AE has received research funding from Pfizer, Eli Lilly, Novartis, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the Simon Spies Foundation and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker from AbbVie, Almirall, Leo Pharma, Zuellig Pharma, Galápagos NV, Sun Pharmaceuticals, Samsung Bioepis, Pfizer, Eli Lilly and Company, Novartis, Union Therapeutics, Galderma, Dermavant, UCB, Mylan, Bristol-Myers Squibb, Horizon Therapeutics and Janssen Pharmaceuticals. UK, Alessandro Cesare Rosa, and Valeria Belleudi are employees of the Department of Epidemiology ASL Roma1, Lazio Regional Health Service in Rome, Italy. Our publicly funded department performs epidemiological research and receives grants from public national and international organisations. In case of financial support from private organisations, an ethical code of conduct is signed to guarantee transparency and independence. KG, DH and JR are employees of the Centre for Pharmacoepidemiology of the Karolinska Institutet in Sweden, which receives grants from regulatory authorities, pharmaceutical companies, and contract research organisations for performance of drug safety and drug utilisation studies. UH, WS and SS are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology-BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. Almost exclusively, these are postauthorisation safety studies (PASS) requested by health authorities. GT declares participation to advisory boards on topics not related to this paper and sponsored by the following pharmaceutical companies in the last two years: Eli Lilly; Sanofi; Amgen; Novo Nordisk; Sobi; Gilead; Celgene; Daikii Sankyo. RG is employed by ARS, a public research centre participating in pharmacoepidemiology studies funded by public or private institutions and compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. Lise Skov Ranch is a full time employee of LEO Pharma A/S., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Psychiatric 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., Objective: To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes., Design, Setting, and Participants: This 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., Exposures: One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs., Main Outcomes and Measures: Any 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., Results: A 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 Relevance: In 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.

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.)

Butyrate and propionate represent two of three main short-chain fatty acids produced by the intestinal microbiota. In healthy populations, their levels are reportedly equimolar, whereas a deviation in their ratio has been observed in various diseased cohorts. Monitoring such a ratio represents a valuable metric; however, it remains a challenge to adopt short-chain fatty acid detection techniques in clinical settings because of the volatile nature of these acids. Here we aimed to estimate short-chain fatty acid information indirectly through a novel, simple quantitative PCR-compatible assay (liquid array diagnostics) targeting a limited number of microbiome 16S markers. Utilizing 15 liquid array diagnostics probes to target microbiome markers selected by a model that combines partial least squares and linear discriminant analysis, the classes (normal vs high propionate-to-butyrate ratio) separated at a threshold of 2.6 with a prediction accuracy of 96%.

Purpose: This study aimed to describe recent trends in ADHD medication use in pregnancy in Norway and Sweden, including prevalence, individual characteristics, and patterns of use., Methods: We studied ADHD medication use (amphetamine, dexamphetamine, methylphenidate, atomoxetine, lisdexamfetamine, guanfacine) by year and age in pregnancies from 2010 to 2019 identified from the medical birth registers (gestational age ≥ 22 weeks) linked to prescribed drug registers (Norway, N = 577,116; Sweden, N = 1,118,988). We compared characteristics of those who used any ADHD medication in pregnancy to no use in pregnancy. Discontinuation was defined as no use after first trimester., Results: ADHD medication use increased from 2010 to 2019 by 3.0 users per 1000 pregnancies in Norway (from 2.5 to 5.5/1000) and by 6.3 per 1000 in Sweden (from 1.6 to 7.9/1000), mainly driven by methylphenidate and since 2015 by lisdexamfetamine. Medication use has increased among pregnant individuals of all age groups, with higher use among the youngest. Pregnant individuals who used ADHD medication were less likely to be married/cohabiting, more likely be nulliparous and to smoke. They had particularly high use of co-medication with antidepressants, anxiolytics/hypnotics, and opioids: 42% in Norway and 65% in Sweden used at least one additional class of psychotropic medication. Most individuals discontinued ADHD medication in pregnancy (85% Norway, 78% Sweden)., Conclusion: ADHD medication use during pregnancy increased in Norway and Sweden in the last decade. However, discontinuation rates during pregnancy were high. Those who used ADHD medication had more risk factors for pregnancy complications including low parity, smoking, and other psychotropic drug use., (© 2022. The Author(s).)

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

Background: Antipsychotics are increasingly used among women of childbearing age and during pregnancy., Objective: To determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders. Design Population-based cohort study, including a sibling analysis. Setting Nationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016). Participants 4 324 086 children were eligible for inclusion to the study cohort. Intervention Antipsychotic exposure in utero , assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use. Main outcome measures Non-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors., Findings: Among 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero . During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD., Discussion: Our findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics., Clinical Implications: Results regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy., Competing Interests: Competing interests: CEC, HK, and JR are employees of the Centre for Pharmacopidemiology at Karolinska Institutet, which receives funding from pharmaceutical companies and regulatory authorities for drug safety/utilisation studies, unrelated to the submitted work. ØK, KF and JMC are employees of an institution, which received funding from pharmaceutical companies to conduct post-authorisation safety studies (PASS) of drugs unrelated to the submitted work (no personal fees). HZ is an employee of the Centre for Big Data Research in Health, UNSW Sydney which received funding from AbbVie Australia to conduct post-marketing drug utilisation research, unrelated to the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: PH and KF were employed by company Genetic Analysis AS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.