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

Objective Pregnant women who develop gestational diabetes (GDM) are more likely to deliver by caesarean section (CS). Over the last decade, the use of metformin has increased as an alternative to insulin but it’s unknown how this shift in treatment has influenced the mode of delivery. Therefore, the aim of this study was to determine the association between metformin use and CS and delivery of a large-for-gestational age (LGA) infant compared to insulin use for GDM. Study design The Swedish population health registers were linked to identify pregnant women from 2012 to 2016 without preexisting diabetes and with a first filled prescription of insulin or metformin in trimester 2 or 3 (n = 2467), categorized into those treated with insulin only (88%), metformin only (7.6%), or both insulin and metformin (4.3%). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Analyses were adjusted for relevant covariates and stratified by history of CS. Results The proportion of women using metformin to treat GDM increased from 2.5% in 2012 to over 30% in 2016. Comparing insulin only to metformin only use, no association with delivery by CS (adjusted OR 0.79, 95% CI; 0.54–1.16) and lower odds of delivering a LGA infant (adjusted OR 0.44, 95% CI; 0.26–0.76) was found. Treatment with both insulin and metformin was associated with an increased risk of CS (adjusted OR 1.65, 95% CI; 1.06–2.56), which were more often unplanned. Estimates were further elevated in nulliparous (adjusted OR 2.32, 95% CI; 0.95–5.65) and multiparous women with a history of CS (adjusted OR 2.29, 95% CI; 0.60–8.74) but conclusions could not be drawn given the wide CIs. Conclusion There was no evidence of a higher association of metformin use alone with CS compared to insulin use for treatment of GDM but a protective effect for delivery of a LGA infant was shown. Women requiring treatment with both insulin and metformin had increased odds for delivery by CS which in turn may indicate that the need for the use of both medications to treat GDM suggests a pregnancy at higher risk.

Aim Continuous use of antidiabetic medication, especially insulin, is crucial for diabetes management. In pregnancy, adherence to medication is generally low and may also be associated with lower socioeconomic status. However, little is known about discontinuation of insulin in pregnant women and the potential role of socioeconomic factors. Therefore, this study aims to measure the associations between socioeconomic factors and insulin discontinuation during pregnancy in women using insulin prior to the start of pregnancy in Sweden. Subjects and methods This cohort study identified pregnancies recorded in the Swedish Medical Birth Register from 2006 to 2016 in women receiving insulin prior to the start of pregnancy (N = 6029). Discontinuation of insulin was defined as not receiving a refill within 120 days from the previous refill. Associations between discontinuation and socioeconomic factors were investigated via logistic regression. Sensitivity analyses were performed using different definitions of discontinuation. Results Women discontinued insulin use in 34.2% of pregnancies. The odds ratios (ORs) of discontinuation of insulin were 1.17 [95% confidence interval (CI): 1.01–1.37] for women with lower household disposable incomes and 1.14 (95% CI: 1.01–1.29) for women with lower educational levels. When testing a change in the maximum refill gap from 91 days to 180 days, women with lower educational levels and those born in non-Nordic countries showed greater associations with discontinuation. Conclusion The definition of discontinuation affects the level of association of socioeconomic factors with discontinuation. Nevertheless, discontinuation of insulin is common in Sweden, especially in the lower socioeconomic groups. The socioeconomic inequality in insulin use behavior is worth noting.

Knowledge on utilization patterns of non-insulin antidiabetic drugs in childhood and youth is limited. Therefore, we conducted a population-based drug utilization study using publicly available aggregate data on use of non-insulin antidiabetics from 2010 to 2019 in Scandinavia (Denmark, Norway and Sweden) in individuals aged up to 24 years. For each non-insulin antidiabetic drug, we calculated the annual prevalence proportion of users, overall and for specific age groups. From 2010 to 2019, the prevalence of non-insulin antidiabetic users in Scandinavia increased 37% from 0.43 to 0.59/1000 individuals. The prevalence proportions were highest among female adolescents and young adults, but the largest relative increase in use was seen among 10-14-year-olds (78%). Metformin was by far the most widely used non-insulin antidiabetic drug with a prevalence proportion of 0.51/1000 in 2019, followed by glucagon-like peptide-1 (GLP-1) analogues, which, however, showed an eight-fold relative increase during the study period.

It is necessary to carry out large observational studies to generate robust evidence about the safety of drugs used during pregnancy. In the Nordic countries, nationwide population-based health registers that document all births and dispensed prescribed drugs are valuable resources for such studies. A common data model (CDM) is a data harmonization and structuring tool that enables a unified and streamlined analytic approach for studies including data from multiple countries or databases. We describe a CDM developed for the Nordic Pregnancy Drug Safety Studies (NorPreSS), including details on data sources and structure of the data tables. We also provide an overview of the advantages and disadvantages of the approach (e.g. sharing of data analysis programs versus extra initial work to create CDM datasets from raw data).

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case–control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1–F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1–F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case–control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations. Prenatal androgen exposure causes transgenerational increases in offspring susceptibility to polycystic ovary syndrome in adulthood.

BackgroundMaternal polycystic ovary syndrome (PCOS) has been proposed as a model for investigating the role of prenatal androgen exposure in the development of neuropsychiatric disorders. However, women with PCOS are at higher risk of developing psychiatric conditions and previous studies are likely confounded by genetic influences.MethodsA Swedish nationwide register-based cohort study was conducted to disentangle the influence of prenatal androgen exposure from familial confounding in the association between maternal PCOS and offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD). PCOS-exposed offspring (n = 21 280) were compared with unrelated PCOS-unexposed offspring (n = 200 816) and PCOS-unexposed cousins (n = 17 295). Associations were estimated with stratified Cox regression models.ResultsPCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring. Associations were stronger in girls for ADHD and ASD but not TD/CTD [ADHD: adjusted hazard ratio (aHR) = 1.61 (95% confidence interval (CI) 1.31–1.99), ASD: aHR = 2.02 (95% CI 1.45–2.82)] than boys [ADHD: aHR = 1.37 (95% CI 1.19–1.57), ASD: aHR = 1.46 (95% CI 1.21–1.76)]. For ADHD and ASD, aHRs for girls were stronger when compared with PCOS-unexposed cousins, but slightly attenuated for boys.ConclusionsEstimates were similar when accounting for familial confounding (i.e. genetics and environmental factors shared by cousins) and stronger in girls for ADHD and ASD, potentially indicating a differential influence of prenatal androgen exposure v. genetic factors. These results strengthen evidence for a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.

Diabetes can be caused by an insufficiency in β-cell mass. Here, we performed a genetic screen in a zebrafish model of β-cell loss to identify pathways promoting β-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated β-cell differentiation in zebrafish. Treatment with folinic acid also stimulated β-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased β-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without β-cell ablation and with/without folinic acid treatment indicated β-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of β-cells., Regeneration of insulin-producing beta-cells may become a future alternative treatment of diabetes. Here the authors report a genetic screen in a zebrafish model that mimics the loss of beta-cells in diabetes, and identified that the folate receptor Folr1 or folinic acid treatment can stimulate beta-cell regeneration.

IntroductionOn February 26th 2020, a high alert was issued in Sweden in response to the diagnosis of the first few coronavirus disease 2019 (COVID-19) cases in the country. Subsequently, a decreased supply of essential goods, including medical products, was anticipated. We aimed to explore the weekly patterns of prescription dispensing and over-the-counter (OTC) medication sales in Sweden in 2020 compared with previous years, to assess the influence of the government restrictions on medication sales, and to assess whether there is evidence of medication stockpiling in the population.MethodsAggregated data on the weekly volume of defined daily doses (DDDs) of prescription medication dispensed and OTC sales from 2015 to 2020 were examined. From 2015-2019 data, the predicted weekly volume of DDDs for 2020 was estimated and compared to the observed volume for each ATC anatomical main group and therapeutic subgroup.ResultsFrom mid-February to mid-March 2020, there were increases in the weekly volumes of dispensed medication, peaking in the second week of March with a 46% increase in the observed versus predicted number of DDDs dispensed (16,440 vs 11,260 DDDs per 1000 inhabitants). A similar pattern was found in all age groups, in both sexes, and across metropolitan and non-metropolitan regions. In the same week in March, there was a 96% increase in the volume of OTC sold (2,504 vs 1,277 DDDs per 1000 inhabitants), specifically in ATC therapeutic subgroups including vitamins, antipyretics, painkillers, and nasal, throat, cough and cold preparations.ConclusionBeginning in mid-February 2020, there were significant changes in the volume of prescription medication dispensed and OTC drugs sold. The weekly volume of DDDs quickly decreased following recommendations from public authorities. Overall, our findings suggest stockpiling behavior over a surge in new users of medication.

Introduction For phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, the only approved indication in women is for pulmonary arterial hypertension. These drugs are increasingly being proposed and tested for treatment of female infertility and complications in pregnancy. However, the extent of use of PDE5 inhibitors in the general pregnant population over the last decades is unknown. Therefore, we conducted a descriptive cohort study using data from the population health registers in the Scandinavian countries. Material and methods By linking the Medical Birth Registers and the Prescribed Drug Registers in Denmark (1997–2017), Norway (2004–2017), and Sweden (2006–2016), women with filled prescriptions of PDE5 inhibitors in outpatient settings in the 90 days before the date of last menstrual period and/or during pregnancies were identified. With additional linkage to the National Patient Registers, information on maternal, pregnancy, and infant characteristics, co-morbidities, and co-medication was collected and described. Results Among over 3 million singleton pregnancies, only 77 were pregnancies in women who had at least one filled prescription of a PDE5 inhibitor within the 90 days before the start of pregnancy to delivery. Prescription fills most often occurred before the last menstrual period and in the first trimester, with very few occurring later in pregnancy. Sildenafil was the most used PDE5 inhibitor. Among pregnant women using PDE5 inhibitors, 44% were 35 years of age or older, eight had a cardiovascular diagnosis, and three specifically had a diagnosis of pulmonary arterial hypertension. Among the infants born to mothers using PDE5 inhibitors, nine were born preterm, six were small-for-gestational age, five had an Apgar score at 5 minutes below 8, 18 were admitted to the Neonatal Intensive Care Unit, and eight had respiratory and cardiovascular conditions. Conclusions Few women used PDE5 inhibitors in outpatient settings before or during pregnancy in the Scandinavian countries in the last decades. Only a small proportion had a diagnosis for pulmonary arterial hypertension, suggesting off-label use in the remaining users. Use was predominantly in mothers over age 35 years. The safety of fetal exposure to sildenafil and other PDE5 inhibitors in pregnancy has not been established. As maternal age continues to increase and additional uses of PDE5 inhibitors are investigated, the safety of these drugs in pregnancy should be thoroughly evaluated. publishedVersion

Background Experimental animal studies suggest a novel role for the folate receptor 1 in β-cell differentiation in the pancreas, with potential implications for glycemic control. Objective We tested the hypothesis of a protective association between prenatal folic acid use and neonatal diabetes or hyperglycemia and type 1 diabetes in an observational cohort study using data from the national population health registers in Norway. Method All singleton pregnancies resulting in livebirths from 2005-2018 were identified. Prenatal exposure to folic acid was determined based on maternal report at antenatal care in early pregnancy. Diagnoses of neonatal diabetes, hyperglycemia, and type 1 diabetes for the children were identified. Associations were estimated with logistic regression or Cox proportional hazard model and included crude and adjusted estimates. Results Amongst 781,567 children, 69% had prenatal exposure to folic acid, 264 were diagnosed with neonatal diabetes or hyperglycemia, and 1390 with type 1 diabetes. Compared to children with no prenatal exposure to folic acid, children with prenatal exposure to folic acid had similar odds of having a neonatal diabetes or hyperglycemia diagnosis (adjusted odds ratio 0.95, 95% confidence interval (CI) 0.72, 1.25) and similar risk of being diagnosed with type 1 diabetes (adjusted hazard ratio 1.05, 95%CI 0.93, 1.18). Conclusion No association between prenatal folic acid exposure and neonatal diabetes/hyperglycemia or type 1 diabetes was found. These findings do not rule out a translational effect of the experimental results and future studies with longer follow-up and more precise information on the window of prenatal exposure are needed. This article is protected by copyright. All rights reserved.

Objective: To compare the risk of ectopic pregnancy among women with and women without antidepressant prescriptions around conception and examine whether this risk differs by prepregnancy depression status. Methods: We conducted a cohort study of all pregnancies between November 1, 2008, and September 30, 2015, identified in the nationwide (American) IBM® MarketScan® Databases. At least one day’s supply of antidepressants in the 3 weeks after a woman’s last menstrual period defined active antidepressant use around conception. At least one depression diagnosis in the year before the last menstrual period defined prepregnancy depression. Relative risk (RR) of ectopic pregnancy was estimated using unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models. Results: Of the 1,703,245 pregnancies, 106,788 (6.3%) women had a prepregnancy depression diagnosis. Among women with a depression diagnosis, 40,287 (37.7%) had an active antidepressant prescription around conception; the IPT-weighted risk of ectopic pregnancy was similar among women who did and did not fill an antidepressant prescription around conception (IPT-weighted RR = 1.01; 95% CI, 0.93 to 1.10). Overall, the risk of ectopic pregnancy was higher among women who had a prepregnancy depression diagnosis than women who did not have a prepregnancy depression diagnosis (IPT-weighted RR = 1.09; 95% CI, 1.04 to 1.15). Conclusions: This study’s findings suggest that women who have a prepregnancy depression diagnosis are at a slightly increased risk of ectopic pregnancy, and among women who have a prepregnancy depression diagnosis, the use of antidepressants around conception does not increase the risk of ectopic pregnancy.

This pharmacoepidemiology study uses Scandinavian birth registry data to estimate the association between modafinil use during early pregnancy and major congenital malformations among infants born in Norway and Sweden between 2005-2006 and 2016-2017.

Introduction Women undergoing fertility treatment experience high levels of stress. However, it remains uncertain if and how stress influences in vitro fertilization (IVF) cycle outcome. This study aimed to investigate whether self-reported perceived and infertility-related stress and cortisol levels were associated with IVF cycle outcomes. Material and methods A prospective cohort of 485 women receiving fertility treatment was recruited from September 2011 to December 2013 and followed until December 2014. Data were collected by online questionnaire prior to IVF start and from clinical charts. Salivary cortisol levels were measured. Associations between stress and cycle outcomes (clinical pregnancy and indicators of oocyte and embryo quality) were measured by logistic or linear regression, adjusted for age, body mass index, education, smoking, alcohol and caffeine consumption, shiftwork and night work. Results Ultrasound verified pregnancy rate was 26.6% overall per cycle started and 32.9% per embryo transfer. Stress measures were not associated with clinical pregnancy: when compared with the lowest categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest categories of the perceived stress score was 1.04 (95% CI 0.58-1.87), infertility-related stress score was OR = 1.18 (95% CI 0.56-2.47), morning and evening cortisol was OR = 1.18 (95% CI 0.60-2.29) and OR = 0.66 (95% CI 0.34-1.30), respectively. Conclusions Perceived stress, infertility-related stress, and cortisol levels were not associated with IVF cycle outcomes. These findings are potentially reassuring to women undergoing fertility treatment with concerns about the influence of stress on their treatment outcome.

Publisher's version (útgefin grein), Purpose: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching. Methods: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester. Results: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%). Conclusions: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED., This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies (NorPreSS) (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366). Linkage of Danish data was supported by the Danish Council for Independent Research (Project No: DFF‐6110‐00019) and Karen Elise Jensens Fond (2016), and grant NNF18OC0052029 from Novo Nordisk Fonden (Li). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). We thank Anders Engeland (Norwegian Institute of Public Health, University of Bergen, Norway), Anna Heino (National Institute for Health and Welfare, Finland), Mette Nørgaard (Aarhus University, Denmark), Pär Karlsson (Karolinska Institutet, Sweden), Jennifer Yland (Harvard T.H. Chan School of Public Health, USA), Gregory Brill and Helen Mogun (Brigham and Women's Hospital & Harvard Medical School, USA) for providing assistance with analyses. The authors would like to thank the NSW Ministry of Health, the Australian Government Department of Health and Ageing and the Department of Human Services for providing data. The authors also thank the Centre for Health Record Linkage (CHeReL) and the Australian Institute for Health and Welfare for conducting the linkage of records.

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

Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting 5-15% of reproductive-aged women and characterized by high levels of circulating androgens. Given that androgens have been implicated in the aetiology of several psychiatric disorders, it was hypothesized that women with PCOS have high risk for psychiatric comorbidity. We aimed to investigate this risk amongst women with PCOS, as well as in their siblings, to elucidate if familial factors underlie any potential associations. Using the Swedish national registers, we identified all women diagnosed with PCOS between 1990 and 2013 (n=24,385), their full-siblings (n=25,921), plus matched individuals (1:10/100) from the general population and their full-siblings. Psychiatric disorder diagnoses were identified including schizophrenia, bipolar disorder, depressive and anxiety disorders, eating disorders, personality and gender identity disorder, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), tics, attempted and completed suicide. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression and adjusted ORs (AOR) were determined by adjustment for comorbid psychiatric disorders. Overall, women with PCOS had an increased odds of having at least one psychiatric disorder (OR=1.56 [95CI%, 1.51-1.61]). Crude ORs showed associations with nearly all psychiatric disorders included in this study. Following adjustment for comorbid psychiatric disorders, women with PCOS were still at a significantly increased risk for bulimia, schizophrenia, bipolar disorder, depressive and anxiety disorders, personality disorders, with the highest AORs for ASD (AOR=1.55 [95%CI, 1.32-1.81]) and tics (AOR=1.65 [95%CI, 1.10-2.47]). Significantly higher AORs were found for ASD in both brothers and sisters of women with PCOS, and for depressive, anxiety, and schizophrenia spectrum disorders in the sisters only. Notably, the crude ORs for attempted suicide were 40% higher in women with PCOS and 16% higher in their unaffected sisters. However, the AORs were greatly attenuated indicating that underlying psychiatric comorbidity is important for this association. Women with PCOS had higher risks for a range of psychiatric disorders not shown before. Elevated risk in their siblings suggests shared familial factors between PCOS and psychiatric disorders. This study is an important first step towards identifying the underlying mechanisms for risk of psychiatric disorders in women with PCOS. Health professionals treating women with PCOS should be aware that these patients - as well as their family members - are important targets for mental health care.

Anorexia nervosa (AN) is a complex and serious eating disorder, occurring in ~1% of individuals. Despite having the highest mortality rate of any psychiatric disorder, little is known about the aetiology of AN, and few effective treatments exist.Global efforts to collect large sample sizes of individuals with AN have been highly successful, and a recent study consequently identified the first genome-wide significant locus involved in AN. This result, coupled with other recent studies and epidemiological evidence, suggest that previous characterizations of AN as a purely psychiatric disorder are over-simplified. Rather, both neurological and metabolic pathways may also be involved.In order to elucidate more of the system-specific aetiology of AN, we applied transcriptomic imputation methods to 3,495 cases and 10,982 controls, collected by the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). Transcriptomic Imputation (TI) methods approaches use machine-learning methods to impute tissue-specific gene expression from large genotype data using curated eQTL reference panels. These offer an exciting opportunity to compare gene associations across neurological and metabolic tissues. Here, we applied CommonMind Consortium (CMC) and GTEx-derived gene expression prediction models for 13 brain tissues and 12 tissues with potential metabolic involvement (adipose, adrenal gland, 2 colon, 3 esophagus, liver, pancreas, small intestine, spleen, stomach).We identified 35 significant gene-tissue associations within the large chromosome 12 region described in the recent PGC-ED GWAS. We applied forward stepwise conditional analyses and FINEMAP to associations within this locus to identify putatively causal signals. We identified four independently associated genes;RPS26, C12orf49, SUOX, andRDH16.We also identified two further genome-wide significant gene-tissue associations, both in brain tissues;REEP5, in the dorso-lateral pre-frontal cortex (DLPFC; p=8.52×10−07), andCUL3, in the caudate basal ganglia (p=1.8×10−06). These genes are significantly enriched for associations with anthropometric phenotypes in the UK BioBank, as well as multiple psychiatric, addiction, and appetite/satiety pathways. Our results support a model of AN risk influenced by both metabolic and psychiatric factors.

Background Women with polycystic ovary syndrome (PCOS) are at elevated risk for suffering from depression. Neuroticism is a personality trait that has been associated with an increased risk for developing major depressive disorder (MDD). The aim of the present study was to quantify and decompose the correlation between neuroticism, PCOS, and MDD into shared and unique genetic and environmental etiologies, by using quantitative genetic methods. Methods In a cohort of 12,628 Swedish female twins born from 1959 to 1985, neuroticism, PCOS identified by symptoms of hyperandrogenemia (i.e., hirsutism) and oligo- and/or anovulation, and lifetime MDD status were determined through questionnaire responses. Structural equation modeling was used to study the genetic and environmental sources of the variation within, and covariation between neuroticism, PCOS, and MDD. Results Female twins with PCOS (n = 752) had significantly higher levels of neuroticism than women without PCOS, and a 2-fold increase in odds for a lifetime prevalence of MDD. The phenotypic correlation between PCOS and MDD was 0.19, with 63% of the correlation attributable to common genetic factors between the two traits. When taking into account neuroticism, 41% was attributable to common genetic factors and 9% attributable to common environmental factors shared between all three traits, with the remainder attributable to components unique to PCOS and MDD. Conclusion There are common genetic factors between neuroticism, PCOS, and MDD; however, neuroticism shares approximately half of the genetic and environmental components behind the phenotypic correlation between PCOS and MDD, providing some etiological evidence behind the comorbidity between PCOS and depression.

PurposeThe Uppsala–Stockholm Assisted Reproductive Techniques (UppStART) study is a prospectively recruited sample of couples undergoing assisted reproduction in Stockholm and Uppsala county in Sweden. The study was initiated to (1) investigate possible changes in the epigenetic profile of infants inferred through the ART procedures and their consequence and (2) to assess the impact of lifestyle and health exposures on treatment outcome.ParticipantsRecruitment took place between September 2011 and December 2013, and in vitro fertilisation (IVF) cycles initiated and pregnancies conceived during this time were followed until December 2014. The cohort includes 971 participants (n= 514 women; n= 457 men), and 129 pregnancies were achieved from the first IVF cycle included in the study.Findings to dateSelf-reported demographic, health and lifestyle data were collected from a baseline questionnaire, and to assess changes to lifestyle, a follow-up questionnaire was issued at the time of oocyte retrieval, and at subsequent IVF cycles. Questionnaire data were linked to data extracted from medical records. Biological samples were collected at baseline: blood for extraction of serum, plasma and DNA, morning and evening saliva samples for cortisol measurement and at delivery including samples of maternal blood, placenta and amniotic fluid, and cord blood for epigenetic analysis.Future plansThrough the unique identification number assigned to each Swedish citizen at birth or immigration, UppStART study participants will be linked to the Swedish population-based national and quality registers to provide data from prenatal, obstetrical, neonatal and infant care, and subsequent updates will provide data on childhood health and educational outcomes. Collaboration and use of UppStART data is encouraged, and more information about access can be found at www.ki.se/meb/uppstart

Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low, minimally toxic doses, with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials and is currently undergoing phase III trial evaluation. It is thought to cause antitumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow–derived cells, including circulating endothelial progenitor cells (CEP). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, antiangiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T-cell responses or by direct antitumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 in nontumor–bearing mice and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6 mg/kg/d), the schedules tested were devoid of toxicity and caused antitumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly, metronomic LY2334737 administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts, and this effect, readily measured using contrast micro-ultrasound, coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant antitumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis. Mol Cancer Ther; 11(3); 680–9. ©2011 AACR.

Smoking during pregnancy has been shown to result in an increased risk of low birth weight. However, the mechanisms underlying this association are poorly understood. The insulin-like growth factor (IGF) system plays a critical role in the regulation of feto-placental growth and development, and abnormal processing of proIGF-II may alter its biological function. Our goal was to investigate the effects of exposure to nicotine on maternal, fetal, and neonatal IGF-II processing. Nulliparous female Wistar rats were randomly assigned to receive saline (vehicle) or nicotine bitartrate (1 mg x kg(-1) x d(- 1)). After mating, dams were euthanized at embryonic days 15, 18, and 21, and fetal body weight was recorded. Serum (fetal and maternal) was collected for determination of the IGF-II profile by Western blot analysis. Nicotine exposure prevented the decrease in maternal IGF-II processing seen in controls with advancing gestation. However, there was no influence of nicotine on fetal levels of IGF-II. Postnatally (postnatal day [PND] 21), pups exposed to nicotine in utero had decreased levels of big IGF-II. Our results show, for the first time, that nicotine exposure prevents the decrease of IGF-II processing in the maternal compartment. This may represent a compensatory mechanism allowing the mother to counteract the negative influence of nicotine on fetal growth and development. Our postnatal findings of suppressed IGF-II may help explain some of the long-term health complications seen in individuals exposed to smoking in utero.

In humans there is evidence that in utero exposure to cigarette smoke results in decreased fertility in female offspring. We have demonstrated in rats that fetal and neonatal exposure to nicotine alone results in impaired fertility and increased follicular atresia in the adult female offspring. In mammals, the insulin-like growth factor-I and -II (IGF-I and -II) and their binding proteins (IGFBPs) are considered stimulators and inhibitors of follicular growth and maturation. Therefore we hypothesized that dysregulation of the intra-ovarian IGF system could be implicated in the impaired fertility observed in nicotine-exposed offspring. Nulliparous female Wistar rats were exposed to nicotine (1 mg/kg/d) for 2 weeks prior to mating until weaning. Ovaries were collected on the morning of estrus from sexually mature saline- and nicotine-exposed offspring. Protein expression of IGF ligands and receptors (IGFR-I and IGFR-II) were quantified by western blot and immunohistochemistry. The expression of IGF-I, IGF-II; IGFR-I, IGFR-II; and IGFBP1–6 mRNA in the ovary was deter- mined by semi-quantitative reverse transcriptase-PCR. Results showed that nicotine exposure significantly reduced IGF-I, IGF-II and IGFR-I protein expression (p < 0.01) relative to saline controls. Furthermore, nicotine-exposed offspring had significantly reduced IGFR-II mRNA expression (p < 0.01) in the ovary. Data from this study suggest that the decreased fertility and increased follicular atresia in nicotine-exposed animals may be due, in part, to disruption of IGF regulation in the ovary.

Objective To investigate associations between depression, anxiety, and antidepressants before in vitro fertilization (IVF) and IVF cycle outcomes, including pregnancy, live birth, and miscarriage. Design Nationwide register-based cohort study. Setting Not applicable. Patient(s) Nulliparous women undergoing their first IVF cycle recorded in the Swedish Quality Register of Assisted Reproduction, January 2007 to December 2012 (n = 23,557). Intervention(s) Not applicable. Main Outcome Measure(s) Associations between diagnoses of depression/anxiety, antidepressants, and IVF cycle outcome evaluated using logistic regression to produce adjusted odds ratios (AOR) and 95% confidence intervals (CI). Result(s) In total, 4.4% of women had been diagnosed with depression/anxiety and/or dispensed antidepressants before their IVF first cycle. The odds for pregnancy and live birth were decreased (n = 1,044; AOR=0.86; 95% CI, 0.75–0.98; and AOR=0.83; 95% CI, 0.72–0.96, respectively). For women with a prescription for a selective serotonin reuptake inhibitor (SSRI) only (n = 829), no statistically significant associations were found. Women with non-SSRI antidepressants (n = 52) were at reduced odds of pregnancy (AOR = 0.41; 95% CI, 0.21–0.80) and live birth (AOR = 0.27; 95% CI, 0.11–0.68). Women with a depression/anxiety diagnosis with no antidepressant (n = 164) also had reduced odds of pregnancy (AOR = 0.58; 95% CI, 0.41–0.82) and live birth (AOR = 0.60; 95% CI, 0.41–0.89). Among the women who became pregnant (39.7%), there were no statistically significant associations between exposure and miscarriage except for the women taking non-SSRI antidepressants (AOR = 3.56; 95% CI, 1.06–11.9). Conclusion(s) A diagnosis of depression/anxiety and/or treatment with antidepressants before IVF was associated with slightly reduced odds of pregnancy and live birth. Women with the presence of depression/anxiety without antidepressants had a more pronounced reduction in odds, implying that the underlying disorder is important for the observed association.