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STUDY QUESTION What is the prospective risk of Type 2 diabetes (T2D) in Nordic women with polycystic ovary syndrome (PCOS) compared to controls? SUMMARY ANSWER A diagnosis of PCOS and BMI ≥30 kg/m2 is a high-risk phenotype for a prospective risk of T2D diagnosis across Nordic countries. WHAT IS KNOWN ALREADY The risk of T2D in women with PCOS is increased. The risk of T2D is related to BMI and the magnitude of risk in normal weight women with PCOS has been discussed. However, prospective data regarding risk of T2D in population-based cohorts of women with PCOS are limited. STUDY DESIGN, SIZE, DURATION This national register-based study included women with PCOS and age-matched controls. The main study outcome was T2D diagnosis occurring after PCOS diagnosis. T2D was defined according to ICD-10 diagnosis codes and/or filled medicine prescriptions of anti-diabetic medication excluding metformin. PARTICIPANTS/MATERIALS, SETTING, METHODS The study cohort included women originating from Denmark (PCOS Denmark, N = 27 016; controls, N = 133 994), Finland (PCOS Finland, N = 20 467; controls, N = 58 051), and Sweden (PCOS Sweden, N = 52 409; controls, N = 254 010). The median age at cohort entry was 28 years in PCOS Denmark, Finland, and Sweden with a median follow-up time (interquartile range) in women with PCOS of 8.5 (4.0–14.8), 9.8 (5.1–15.1), and 6.0 (2.0–10.0) years, respectively. Cox regression analyses were adjusted for BMI and length of education. MAIN RESULTS AND THE ROLE OF CHANCE The crude hazard ratio (HR, 95% CI) for T2D diagnosis in women with PCOS was 4.28 (3.98–4.60) in Denmark, 3.40 (3.11–3.74) in Finland, and 5.68 (5.20–6.21) in Sweden. In adjusted regression analyses, BMI ≥30 vs <25 kg/m2 was associated with a 7.6- to 11.3-fold risk of T2D. In a combined meta-analysis (PCOS, N = 99 892; controls, N = 446 055), the crude HR for T2D in PCOS was 4.64 (3.40–5.87) and, after adjustment for BMI and education level, the HR was 2.92 (2.32–3.51). LIMITATIONS, REASONS FOR CAUTION Inclusion of more severe cases of PCOS in the present study design could have lead to an overestimation of risk estimates in our exposed population. However, some women in the control group would have undiagnosed PCOS, which would lead to an underestimation of T2D risk in women with PCOS. BMI data were not available for all participants. The present study should be repeated in study cohorts with higher background risks of T2D, particularly in populations of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS The prospective risk for diagnosis of T2D is increased in women with PCOS, and the risk is aggravated in women with BMI ≥30 kg/m2. STUDY FUNDING/COMPETING INTEREST(S) Funding in Denmark was from the Region of Southern Denmark, Overlægerådet, Odense University Hospital. Funding in Finland was from Novo Nordisk Foundation, Finnish Research Council and Sigrid Juselius Foundation, the National Regional Fund, Sakari Alhopuro Foundation and Finnish Diabetes Research Foundation. E.E. has received a research grant from Ferring Pharmaceuticals (payment to institution) and serves as medical advisor for Tilly AB, not related to this manuscript. The remaining authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

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

Introduction: The Coronavirus 2019 Disease (COVID‐19) pandemic reached the Nordic countries in March 2020. Public health interventions to limit viral transmission varied across different countries both in timing and in magnitude. Interventions indicated by an Oxford Stringency Index ≥50 were implemented early (March 13–17, 2020) in Denmark, Finland, Norway and Iceland, and on March 26, 2020 in Sweden. The aim of the current study was to assess the incidence of COVID‐19‐related admissions of pregnant women in the Nordic countries in relation to the different national public health strategies during the first year of the pandemic. Material and methods: This is a meta‐analysis of population‐based cohort studies in the five Nordic countries with national or regional surveillance in the Nordic Obstetric Surveillance System (NOSS) collaboration: national data from Denmark, Finland, Iceland and Norway, and regional data covering 31% of births in Sweden. The source population consisted of women giving birth in the included areas March 1–December 31, 2020. Pregnant women with a positive SARS‐CoV‐2 PCR test ≤14 days before hospital admission were included, and admissions were stratified as either COVID‐19‐related or non‐COVID (other obstetric healthcare). Information about public health policies was retrieved retrospectively. Results: In total, 392 382 maternities were considered. Of these, 600 women were diagnosed with SARS‐CoV‐2 infection and 137 (22.8%) were admitted for COVID‐19 symptoms. The pooled incidence of COVID‐19 admissions per 1000 maternities was 0.5 (95% confidence interval [CI] 0.2 to 1.2, I2 = 77.6, tau2 = 0.68, P = 0.0), ranging from no admissions in Iceland to 1.9 admissions in the Swedish regions. Interventions to restrict viral transmission were less stringent in Sweden than in the other Nordic countries. Conclusions: There was a clear variation in pregnant women's risk of COVID‐19 admission across countries with similar healthcare systems but different public health interventions to limit viral transmission. The meta‐analysis indicates that early suppression policies protected pregnant women from severe COVID‐19 disease prior to the availability of individual protection with vaccines. [ABSTRACT FROM AUTHOR]

The International Collaboration for Autism Registry Epidemiology (iCARE) is the first multinational research consortium (Australia, Denmark, Finland, Israel, Norway, Sweden, USA) to promote research in autism geographical and temporal heterogeneity, phenotype, family and life course patterns, and etiology. iCARE devised solutions to challenges in multinational collaboration concerning data access security, confidentiality and management. Data are obtained by integrating existing national or state-wide, population-based, individual-level data systems and undergo rigorous harmonization and quality control processes. Analyses are performed using database federation via a computational infrastructure with a secure, web-based, interface. iCARE provides a unique, unprecedented resource in autism research that will significantly enhance the ability to detect environmental and genetic contributions to the causes and life course of autism.

Background: Stillbirth has been associated with low plasma vitamin D. Both Sweden and Finland have a high proportion of low plasma vitamin D levels (< 50 nmol/L). We aimed to assess the odds of stillbirth in relation to changes in national vitamin D fortification. Methods: We surveyed all pregnancies in Finland between 1994 and 2021 (n = 1,569,739) and Sweden (n = 2,800,730) with live or stillbirth registered in the Medical Birth Registries. The mean incidences before and after changes in the vitamin D food fortification programs in Finland (2003 and 2009) and Sweden (2018) were compared with cross-tabulation with 95% confidence intervals (CI). Results: In Finland, the stillbirth rate declined from ~ 4.1/1000 prior to 2003, to 3.4/1000 between 2004 and 2009 (odds ratio [OR] 0.87, 95% CI 0.81–0.93), and to 2.8/1000 after 2010 (OR 0.84, 95% CI 0.78–0.91). In Sweden, the stillbirth rate decreased from 3.9/1000 between 2008 and 2017 to 3.2/1000 after 2018 (OR 0.83, 95% CI 0.78–0.89). When the level of the dose-dependent difference in Finland in a large sample with correct temporal associations decreased, it remained steady in Sweden, and vice versa, indicating that the effect may be due to vitamin D. These are observational findings that may not be causal. Conclusion: Each increment of vitamin D fortification was associated with a 15% drop in stillbirths on a national level. If true, and if fortification reaches the entire population, it may represent a milestone in preventing stillbirths and reducing health inequalities. [ABSTRACT FROM AUTHOR]

Purpose The primary aim of this study was to observe the change in obstetric anal sphincter tear rates in instrumental deliveries during one decade. Secondly, the changes in non-instrumental deliveries were followed. Methods Data from all deliveries at Hudiksvall Hospital, Sweden 2010–2011 and 2016–2017 were collected. The change of OASIS rate during instrumental deliveries was the most important. Statistical significances were calculated by using chi-square test, test for relative proportions, and Students t-test, where appropriate. Results The total incidence of OASIS decreased significantly (from 2.54% to 0.73%, p < .001). Even the OASIS rate in instrumental deliveries decreased substantially from 15.1% to 3.0% (p = .002) but the decrease was statistically insignificant in spontaneous deliveries (from 1.22% to 0.60%, p = .065). Conclusion Based on the results of our study the manual protection of the perineum reduces the risk of OASIS in instrumental delivery significantly. [ABSTRACT FROM AUTHOR]

Research suggests that adult children of parents with harmful alcohol use are at increased risk for premature death. This national cohort study investigated mortality in adult children of parents with alcohol use disorder (AUD), adjusting for sociodemographic variables. The study used 1973 to 2018 data from Swedish national registers to compare mortality risk in children who had ≥ 1 parent with AUD (ICD-10 code F10 and its ICD-8 and ICD-9 equivalents) (n = 122,947) and those who did not (n = 2,298,532). A Cox regression model adjusted for year of birth, sex, parental education, and childhood loss of a parent was used. Before the age of 18 years, about 5% of children born in Sweden lived with ≥ 1 parent who had a clinical diagnosis of AUD. Overall mortality was higher in adult children of parents with AUD: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.71–1.82. Mortality remained elevated after adjustments for sociodemographic factors (HR 1.45, 95% CI 1.40–1.50). Children of parents with AUD had increased mortality from all investigated causes. The highest excess risk was for death from drug-related causes (excluding accidental poisonings) (HR 3.08, 95% CI 2.74–3.46). For most causes, mortality was higher if the mother had AUD than if the father had AUD. Patterns of mortality were similar in both sexes. This study provides evidence that parental AUD raises the risk of offspring mortality from preventable causes such as drug use, suicide (HR 2.16, 95% CI 1.98–2.36), accident (HR 2.00, 95% CI 1.87–2.13), and assault (HR 1.76, 95% CI 1.38–2.24). [ABSTRACT FROM AUTHOR]

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 liveborn 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. [ABSTRACT FROM AUTHOR]

Background: Compared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors.Methods and Findings: This registry-based cohort study with nationwide data from Denmark (1994-2014), Norway (1988-2015), and Sweden (1988-2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (-51 g, 95% CI -58 to -45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (-1.0 days, 95% CI -1.2 to -0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking.Conclusions: We found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.Trial Registration: ClinicalTrials.gov ISRCTN11780826. [ABSTRACT FROM AUTHOR]

Maternal hypertensive disorders during pregnancy (HDP) have been associated with neuropsychiatric problems in offspring. We aim to investigate the associations between specific types of maternal HDP and offspring neurodevelopmental disorders and further examine whether the timing of onset and severity of HDP would affect these associations. The study population consisted of 4,489,044 live-born singletons in Denmark during 1978–2012 and Sweden during 1987–2010. Maternal HDP was categorized into chronic hypertension, gestational hypertension, and pre-eclampsia; pre-eclampsia was further stratified according to timing (early-onset, late-onset), or severity (moderate, severe) of the disease. Neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), were defined by ICD-coded register diagnosis. Cox regression was used to calculate hazard ratios (HR) while adjusting for potential confounders, and sibling analyses assessed the influence of unmeasured shared familial factors. Maternal HDP was associated with increased risks of ADHD (HR, 1.24; 95% confidence interval [CI], 1.20–1.28), ASD (1.29 [1.24–1.34]), and ID (1.58 [1.50–1.66]) in offspring, respectively, which was mostly driven by pre-eclampsia. The strongest associations were observed for early-onset and severe pre-eclampsia, and the corresponding HRs for ADHD, ASD and ID were 1.93 [1.73–2.16], 1.86 [1.61–2.15], and 3.99 [3.42–4.65], respectively. The results were similar in the sibling analyses. The associations between maternal HDP and offspring neurodevelopmental disorders were consistent across the subgroups of sex, preterm status, parity, maternal age and psychiatric disorders. Maternal HDP, especially early-onset pre-eclampsia, are associated with increased risks of ADHD, ASD, and ID in particular, independent of shared familial factors. [ABSTRACT FROM AUTHOR]

Study Question: Is maternal polycystic ovary syndrome (PCOS) associated with increased risks for a broad spectrum of psychiatric and mild neurodevelopmental disorders in offspring?Summary Answer: Maternal PCOS and/or anovulatory infertility is independently, and jointly with maternal obesity, perinatal problems, cesarean delivery and gestational diabetes, associated with increased risks in offspring for almost all groups of psychiatric and mild neurodevelopmental disorders with onset in childhood or adolescence.What Is Known Already: Maternal PCOS was previously associated with autism spectrum disorder, attention-deficit/hyperactivity disorders and possibly developmental delay in offspring. Few studies have investigated the association between maternal PCOS and other psychiatric and neurodevelopmental disorders in offspring.Study Design, Size, Duration: This was a population-based cohort study in Finland including all live births between 1996 and 2014 (n = 1 105 997). After excluding births to mothers with symptoms similar to PCOS, a total of 1 097 753 births by 590 939 mothers remained. Children were followed up until 31 December 2018, i.e. up to the age of 22 years.Participants/materials, Setting, Methods: National registries were used to link data of the included births and their mothers. Data from 24 682 (2.2%) children born to mothers with PCOS were compared with 1 073 071 (97.8%) children born to mothers without PCOS. Cox proportional hazards modeling was used to evaluate the hazard ratio (HR) and 95% CI for the risk of neuropsychiatric disorders in relation to maternal PCOS. Stratified analyses were performed to test the independent role of PCOS and the joint effects of PCOS with maternal obesity, perinatal problems, cesarean delivery, gestational diabetes and use of fertility treatment. The analysis was adjusted for maternal age, country of birth, marriage status at birth, smoking, parity, psychiatric disorders, prescription of psychotropic N05/N06 during pregnancy and systemic inflammatory diseases when applicable.Main Results and the Role Of Chance: A total of 105 409 (9.8%) children were diagnosed with a neurodevelopmental or psychiatric disorder. Firstly, maternal PCOS was associated with any psychiatric diagnosis (HR 1.32; 95% CI 1.27-1.38) in offspring. Particularly, the risk was increased for sleeping disorders (HR 1.46; 95% CI 1.27-1.67), attention-deficit/hyperactivity disorders and conduct disorders (HR 1.42; 95% CI 1.33-1.52), tic disorders (HR 1.42; 95% CI 1.21-1.68), intellectual disabilities (HR 1.41; 95% CI 1.24-1.60), autism spectrum disorder (HR 1.40; 95% CI 1.26-1.57), specific developmental disorders (HR 1.37; 95% CI 1.30-1.43), eating disorders (HR 1.36; 95% CI 1.15-1.61), anxiety disorders (HR 1.33; 95% CI 1.26-1.41), mood disorders (HR 1.27; 95% CI 1.18-1.35) and other behavioral and emotional disorders (ICD-10 F98, HR 1.49; 95% CI 1.39-1.59). In short, there was no significant difference between sexes. The results were robust when restricting the analyses to the first-born children or births to mothers without psychiatric diagnosis or purchase of psychotropic medication. Secondly, stratified analysis according to maternal BMI showed that the risk of any neuropsychiatric disorder was increased in offspring to normal-weight mothers with PCOS (HR 1.20; 95% CI 1.09-1.32), and markedly higher in those to severely obese mothers with PCOS (HR 2.11; 95% CI 1.76-2.53) compared to offspring to normal-weight mothers without PCOS. When excluding perinatal problems, mothers with PCOS were still associated with increased risks of any neuropsychiatric disorders in offspring (HR 1.28; 95% CI 1.22-1.34) compared to mothers without PCOS. However, an additional increase was observed for PCOS in combination with perinatal problems (HR 1.99; 95% CI 1.84-2.16). Likewise, excluding cases with maternal gestational diabetes (HR 1.30; 95% CI 1.25-1.36), cesarean delivery (HR 1.29; 95% CI 1.23-1.35) or fertility treatment (HR 1.31; 95% CI 1.25-1.36) did not eliminate the associations.Limitations, Reasons For Caution: The register-based prevalence of PCOS was lower than previously reported, suggesting that this study may capture the most severe cases. To combine anovulatory infertility with PCOS diagnosis as PCOS exposure might introduce diagnostic bias. It was not feasible to distinguish between subtypes of PCOS. Furthermore, familial factors might confound the association between maternal PCOS and neuropsychiatric disorders in offspring. Maternal BMI was available for birth cohort 2004-2014 only and there was no information on gestational weight gain.Wider Implications Of the Findings: This study provides further evidence that maternal PCOS and/or anovulatory infertility, independently and jointly with maternal obesity, perinatal problems, gestational diabetes and cesarean delivery, implies a broad range of adverse effects on offspring neurodevelopment. These findings may potentially help in counseling and managing pregnancies.Study Funding/competing Interest(s): This study was supported by the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C and C.L.), THL Finnish Institute for Health and Welfare: Drug and pregnancy project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. was supported by the China Scholarship Council during her training in Karolinska Institute. L.K. was supported by the China Scholarship Council for his PhD study in Karolinska Institute. The authors have no competing interests to disclose.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Introduction: The complex etiology of autism spectrum disorder (ASD) is still unresolved. Preterm birth (<37 weeks of gestation) and its complications are the leading cause of death of babies in the world, and those who survive often have long-term health problems. Length of gestation, including preterm birth, has been linked to ASD risk, but robust estimates for the whole range of gestational ages (GAs) are lacking. The primary objective of this study was to provide a detailed and robust description of ASD risk across the entire range of GAs while adjusting for sex and size for GA.Methods and Findings: Our study had a multinational cohort design, using population-based data from medical registries in three Nordic countries: Sweden, Finland, and Norway. GA was estimated in whole weeks based on ultrasound. Children were prospectively followed from birth for clinical diagnosis of ASD. Relative risk (RR) of ASD was estimated using log-binomial regression. Analyses were also stratified by sex and by size for GA. The study included 3,526,174 singletons born 1995 to 2015, including 50,816 (1.44%) individuals with ASD. In the whole cohort, 165,845 (4.7%) were born preterm. RR of ASD increased by GA, from 40 to 24 weeks and from 40 to 44 weeks of gestation. The RR of ASD in children born in weeks 22-31, 32-36, and 43-44 compared to weeks 37-42 were estimated at 2.31 (95% confidence interval [CI] 2.15-2.48; 1.67% vs 0.83%; p-value < 0.001), 1.35 (95% CI 1.30-1.40; 1.08% vs 0.83%; p-value < 0.001), and 1.37 (95% CI 1.21-1.54; 1.74% vs 0.83%; p-value < 0.001), respectively. The main limitation of this study is the lack of data on potential causes of pre- or postterm birth. Also, the possibility of residual confounding should be considered.Conclusion: In the current study, we observed that the RR of ASD increased weekly as the date of delivery diverged from 40 weeks, both pre- and postterm, independently of sex and size for GA. Given the unknown etiology of ASD and the lifelong consequences of the disorder, identifying groups of increased risk associated with a potentially modifiable risk factor is important.Author Summary: [ABSTRACT FROM AUTHOR]

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

Study Question: Is transfer of vitrified blastocysts associated with higher perinatal and maternal risks compared with slow-frozen cleavage stage embryos and fresh blastocysts?Summary Answer: Transfer of vitrified blastocysts is associated with a higher risk of preterm birth (PTB) when compared with slow-frozen cleavage stage embryos and with a higher risk of a large baby, hypertensive disorders in pregnancy (HDPs) and postpartum hemorrhage (PPH) but a lower risk of placenta previa when compared with fresh blastocysts.What Is Known Already: Transfer of frozen-thawed embryos (FETs) plays a central role in modern fertility treatment, limiting the risk of ovarian hyperstimulation syndrome and multiple pregnancies. Following FET, several studies report a lower risk of PTB, low birth weight (LBW) and small for gestational age (SGA) yet a higher risk of fetal macrosomia and large for gestational age (LGA) compared with fresh embryos. In recent years, the introduction of new freezing techniques has increased treatment success. The slow-freeze technique combined with cleavage stage transfer has been replaced by vitrification and blastocyst transfer. Only few studies have compared perinatal and maternal outcomes after vitrification and slow-freeze and mainly in cleavage stage embryos, with most studies indicating similar outcomes in the two groups. Studies on perinatal and maternal outcomes following vitrified blastocysts are limited.Study Design, Size, Duration: This registry-based cohort study includes singletons born after frozen-thawed and fresh transfers following the introduction of vitrification in Sweden and Denmark, in 2002 and 2009, respectively. The study includes 3650 children born after transfer of vitrified blastocysts, 8123 children born after transfer of slow-frozen cleavage stage embryos and 4469 children born after transfer of fresh blastocysts during 2002-2015. Perinatal and maternal outcomes in singletons born after vitrified blastocyst transfer were compared with singletons born after slow-frozen cleavage stage transfer and singletons born after fresh blastocyst transfer. Main outcomes included PTB, LBW, macrosomia, HDP and placenta previa.Participants/materials, Setting, Methods: Data were obtained from the CoNARTaS (Committee of Nordic ART and Safety) group. Based on national registries in Sweden, Finland, Denmark and Norway, the CoNARTaS cohort includes all children born after ART treatment in public and private clinics 1984-2015. Outcomes were assessed with logistic multivariable regression analysis, adjusting for the country and year of birth, maternal age, body mass index, parity, smoking, parental educational level, fertilisation method (IVF/ICSI), single embryo transfer, number of gestational sacs and the child's sex.Main Results and the Role Of Chance: A higher risk of PTB (<37 weeks) was noted in the vitrified blastocyst group compared with the slow-frozen cleavage stage group (adjusted odds ratio, aOR [95% CI], 1.33 [1.09-1.62]). No significant differences were observed for LBW (<2500 g), SGA, macrosomia (≥4500 g) and LGA when comparing the vitrified blastocyst with the slow-frozen cleavage stage group. For maternal outcomes, no significant difference was seen in the risk of HDP, placenta previa, placental abruption and PPH in the vitrified blastocyst versus the slow frozen cleavage stage group, although the precision was limited.When comparing vitrified and fresh blastocysts, we found higher risks of macrosomia (≥4500 g) aOR 1.77 [1.35-2.31] and LGA aOR 1.48 [1.18-1.84]. Further, the risks of HDP aOR 1.47 [1.19-1.81] and PPH aOR 1.68 [1.39-2.03] were higher in singletons born after vitrified compared with fresh blastocyst transfer while the risks of SGA aOR 0.58 [0.44-0.78] and placenta previa aOR 0.35 [0.25-0.48] were lower.Limitations, Reasons For Caution: Since vitrification was introduced simultaneously with blastocyst transfer in Sweden and Denmark, it was not possible to explore the effect of vitrification per se in this study.Wider Implications Of the Findings: The results from the change of strategy to vitrification of blastocysts are reassuring, indicating that the freezing technique per se has no major influence on the perinatal and maternal outcomes. The higher risk of PTB may be related to the extended embryo culture rather than vitrification.Study Funding/competing Interest(s): The study is part of the ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. The study was also financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation and NordForsk (project 71 450). There are no conflicts of interest to declare.Trial Registration Number: ISRCTN11780826. [ABSTRACT FROM AUTHOR]

Importance: The origins and development of autism spectrum disorder (ASD) remain unresolved. No individual-level study has provided estimates of additive genetic, maternal, and environmental effects in ASD across several countries.Objective: To estimate the additive genetic, maternal, and environmental effects in ASD.Design, Setting, and Participants: Population-based, multinational cohort study including full birth cohorts of children from Denmark, Finland, Sweden, Israel, and Western Australia born between January 1, 1998, and December 31, 2011, and followed up to age 16 years. Data were analyzed from September 23, 2016 through February 4, 2018.Main Outcomes and Measures: Across 5 countries, models were fitted to estimate variance components describing the total variance in risk for ASD occurrence owing to additive genetics, maternal, and shared and nonshared environmental effects.Results: The analytic sample included 2 001 631 individuals, of whom 1 027 546 (51.3%) were male. Among the entire sample, 22 156 were diagnosed with ASD. The median (95% CI) ASD heritability was 80.8% (73.2%-85.5%) for country-specific point estimates, ranging from 50.9% (25.1%-75.6%) (Finland) to 86.8% (69.8%-100.0%) (Israel). For the Nordic countries combined, heritability estimates ranged from 81.2% (73.9%-85.3%) to 82.7% (79.1%-86.0%). Maternal effect was estimated to range from 0.4% to 1.6%. Estimates of genetic, maternal, and environmental effects for autistic disorder were similar with ASD.Conclusions and Relevance: Based on population data from 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences, with no support for contribution from maternal effects. The results suggest possible modest differences in the sources of ASD risk between countries. [ABSTRACT FROM AUTHOR]

Aim: We investigated mortality from external causes in Swedish people who had been hospitalised with a severe mental disorder. Methods: Hospitalisations in people aged 15 years or older admitted to hospital with a main diagnosis of schizophrenia, bipolar mood disorder or unipolar mood disorder between 1987 and 2010 were linked to their causes of death. Results: The mortality rate from all external causes was 20-fold higher in those with unipolar mood disorder, 15-fold higher in those with bipolar disorder and 12-fold higher in those with schizophrenia than in the general population. Over the study periods, the mortality rate declined more for people with unipolar mood disorder (−35%) and schizophrenia (−29%) than the total population (−25%) and those with bipolar mood disorder (−15%). The suicide rate declined most for those with unipolar mood disorder and schizophrenia (−42% for both) and less for the general population (−37%) and those with bipolar mood disorder (−21%). For external causes other than suicide, the mortality rate declined in the general population (−17%) but increased in people with schizophrenia (14%), bipolar mood disorder (30%) and unipolar mood disorder (52%). Conclusions: People with mental disorders have high but declining excess mortality from suicide. Mortality from other external causes has increased, as has the gap in mortality rates between psychiatric patients and the general population. [ABSTRACT FROM AUTHOR]

Background: Gestational age estimation by last menstrual period (LMP) vs. ultrasound (or best obstetric estimate in the US) may result in discrepant classification of preterm vs. term birth. We investigated whether such discrepancies are associated with adverse infant outcomes.Methods: We studied singleton livebirths in the Medical Birth Registries of Norway, Sweden and Finland and US live birth certificates from 1999 to the most recent year available. Risk ratios (RR) with 95% confidence intervals (CI) by discordant and concordant gestational age estimation for infant, neonatal and post-neonatal mortality, Apgar score <4 and <7 at 5 min, and neonatal intensive care unit (NICU) admission were estimated using generalised linear models, adjusting for maternal age, education, parity, year of birth, and infant sex. Results were presented stratified by country.Results: Compared to infants born at term by both methods, infants born preterm by ultrasound/best obstetric estimate but term by LMP had higher infant mortality risks (range of adjusted RRs 3.9 to 7.2) and modestly higher risks were obtained among infants born preterm by LMP but term by ultrasound/best obstetric estimate (range of adjusted RRs 1.6 to 1.9). Risk estimates for the other outcomes showed the same pattern. These findings were consistent across all four countries.Conclusions: Infants classified as preterm by ultrasound/best estimate, but term by LMP have consistently higher risks of adverse outcomes than those classified as preterm by LMP but term by ultrasound/best estimate. Compared with ultrasound/best estimate, use of LMP overestimates the proportion of births that are preterm. [ABSTRACT FROM AUTHOR]

Introduction: People with severe mental illness have increased risk for premature mortality and thus a shorter life expectancy. Relative death rates are used to show the excess mortality among patients with mental health disorder but cannot be used for the comparisons by country, region and time. Methods: A population-based register study including all Swedish patients in adult psychiatry admitted to hospital with a main diagnosis of schizophrenia, bipolar or unipolar mood disorder in 1987-2010 (614 035 person-years). Mortality rates adjusted for age, sex and period were calculated using direct standardization methods with the 2010 Swedish population as standard. Data on all residents aged 15 years or older were used as the comparison group. Results: Patients with severe mental health disorders had a 3-fold mortality compared to general population. All-cause mortality decreased by 9% for people with bipolar mood disorder and by 26-27% for people with schizophrenia or unipolar mood disorder, while the decline in the general population was 30%. Also mortality from diseases of the circulatory system declined less for people with severe mental disorder (-35% to -42%) than for general population (49%). The pattern was similar for other cardiovascular deaths excluding cerebrovascular deaths for which the rate declined among people with schizophrenia (-30%) and unipolar mood disorder (-41%), unlike for people with bipolar mood disorder (-3%). Conclusions: People with mental health disorder have still elevated mortality. The mortality declined faster for general population than for psychiatric patients. More detailed analysis is needed to reveal causes-of-death with largest possibilities for improvement. [ABSTRACT FROM AUTHOR]

Importance: Clinicians have been urged to delay the use of obstetric interventions (eg, labor induction, cesarean delivery) until 39 weeks or later in the absence of maternal or fetal indications for intervention.Objective: To describe recent trends in late preterm and early term birth rates in 6 high-income countries and assess association with use of clinician-initiated obstetric interventions.Design: Retrospective analysis of singleton live births from 2006 to the latest available year (ranging from 2010 to 2015) in Canada, Denmark, Finland, Norway, Sweden, and the United States.Exposures: Use of clinician-initiated obstetric intervention (either labor induction or prelabor cesarean delivery) during delivery.Main Outcomes and Measures: Annual country-specific late preterm (34-36 weeks) and early term (37-38 weeks) birth rates.Results: The study population included 2,415,432 Canadian births in 2006-2014 (4.8% late preterm; 25.3% early term); 305,947 Danish births in 2006-2010 (3.6% late preterm; 18.8% early term); 571,937 Finnish births in 2006-2015 (3.3% late preterm; 16.8% early term); 468,954 Norwegian births in 2006-2013 (3.8% late preterm; 17.2% early term); 737,754 Swedish births in 2006-2012 (3.6% late preterm; 18.7% early term); and 25,788,558 US births in 2006-2014 (6.0% late preterm; 26.9% early term). Late preterm birth rates decreased in Norway (3.9% to 3.5%) and the United States (6.8% to 5.7%). Early term birth rates decreased in Norway (17.6% to 16.8%), Sweden (19.4% to 18.5%), and the United States (30.2% to 24.4%). In the United States, early term birth rates decreased from 33.0% in 2006 to 21.1% in 2014 among births with clinician-initiated obstetric intervention, and from 29.7% in 2006 to 27.1% in 2014 among births without clinician-initiated obstetric intervention. Rates of clinician-initiated obstetric intervention increased among late preterm births in Canada (28.0% to 37.9%), Denmark (22.2% to 25.0%), and Finland (25.1% to 38.5%), and among early term births in Denmark (38.4% to 43.8%) and Finland (29.8% to 40.1%).Conclusions and Relevance: Between 2006 and 2014, late preterm and early term birth rates decreased in the United States, and an association was observed between early term birth rates and decreasing clinician-initiated obstetric interventions. Late preterm births also decreased in Norway, and early term births decreased in Norway and Sweden. Clinician-initiated obstetric interventions increased in some countries but no association was found with rates of late preterm or early term birth. [ABSTRACT FROM AUTHOR]

Background: Early discontinuation of anti-depressant treatment is common. This study analysed whether socio-economic factors influence early discontinuation among new anti-depressant users aged 20–34 years. Methods: Our study population included all Swedes aged 20–34 years who purchased anti-depressants in 2006 and had not purchased such drugs in the preceding 6 months (n = 25 003). We obtained prescription data from the Swedish Prescribed Drug Register. Information about demographic and socio-economic factors (country of birth, marital status, household size, education level, occupation, income and social assistance) was collected from Statistics Sweden by record linkage. We defined early discontinuation as filling only one anti-depressant prescription within a 6-month period. We used multiple logistic regression analysis to analyse the socio-economic factors associated with early discontinuation. Results: We identified 6536 individuals (26.1%) as early discontinuers. Early discontinuation was less common among women [odds ratio (OR) = 0.82; 95% confidence intervals (CI) 0.75–0.87] and in those with at least two years of higher education (OR = 0.71; 95% CI 0.61–0.83), whereas it was more common among those born outside Sweden (OR = 1.76; 95% CI 1.48–2.10) and those who received social assistance (OR = 1.26; 95% CI 1.11–1.44). Compared with selective serotonin re-uptake inhibitors, SSRI, early discontinuation was more common among individuals who started treatment with a tri-cyclic anti-depressant, TCA, (OR = 2.58; 95% CI 2.24–2.98) or an anti-depressant other than SSRIs, TCAs or selective serotonin-norepinephrine re-uptake inhibitors/norepinephrine (noradrenaline) re-uptake inhibitors (OR = 2.90; 95% CI 2.05–4.10). Conclusion: Early discontinuation occurred more commonly among social assistance recipients and those with immigrant background, suggesting that those groups might require greater support when initiating anti-depressant therapy. [ABSTRACT FROM PUBLISHER]

Background The stillbirth rates in Denmark, Finland, Norway and Sweden are among the lowest in the world, but socioeconomic disparities in stillbirth still exist. This study examined the educational patterns in the risk of stillbirth in Denmark, Finland, Norway and Sweden from 1981 to 2000. Methods From the national birth registries, all singleton live births and stillbirths with a gestational age of at least 28 weeks were selected in Denmark (n=1 182 888), Finland (n=419 729), Norway (n=1 006 767) and Sweden (n=1 974 101). The births were linked with individual data on parental socioeconomic factors from various national registers. Linear and logistic regression were used to calculate RR and risk differences for stillbirth according to maternal educational attainment. Results The risk of stillbirth was lowest in Finland and highest in Denmark. The risk decreased over time in Denmark, Norway and Finland, but remained stable in Sweden. Educational gradients were found in all countries in all time periods under study. In Denmark, the gradient remained stable over time. In Norway the gradient decreased slightly during the 1990s, whereas the gradient increased in Sweden. The gradient in Finland was relatively stable. Conclusions There were persisting educational inequalities in stillbirth in Denmark, Finland, Norway and Sweden in the 1980s and 1990s. Inequalities were stable or decreasing except in Sweden, where an increase in inequality was observed. This increase was not solely attributable to a decreasing absolute risk of stillbirth as both the relative and absolute measures of inequality increased. [ABSTRACT FROM AUTHOR]

Background Socioeconomic position inequalities in infant mortality are well known, but there is less information on how child mortality is socially patterned by sex and age. Objective To assess maternal and paternal socioeconomic inequalities in mortality by sex, whether these differences vary by age and country, and how much of the sex differences can be explained by external causes of death. Methods Data on all live-born children were received from national birth registries for 1981-2000 (Denmark: n=1 184 926; Norway: n=1 090 127; and Sweden n=1 961 911) and for 1987-2000 (Finland: n=841 470). Data on the highest level of education in 2000 were obtained from national education registers, and data on mortality and causes of death were received from the national cause-of-death registers until the end of follow-up (20 years or 2003). Results Boys had a higher child and adolescent mortality than girls. The children of mothers and fathers who had had the shortest education time had the highest mortality for both sexes and for all ages and countries. The differences between the groups with longer than basic education were smaller, particularly among older children and girls. The gradient in mortality was mostly similar for boys and girls. Among 1-19-year-olds, 32% of boys' deaths and 27% of girls' deaths were due to external causes. Conclusion Boys' excess mortality was only partly explained by educational inequalities or by deaths from external causes. A more detailed analysis is needed to study whether the share of avoidable deaths is higher among children whose parents have had a shorter education time. [ABSTRACT FROM AUTHOR]

Background: People with mental disorders evince excess mortality due to natural and unnatural deaths. The relative life expectancy of people with mental disorders is a proxy measure of effectiveness of social policy and health service provision.Aims: To evaluate trends in health outcomes of people with serious mental disorders.Method: We examined nationwide 5-year consecutive cohorts of people admitted to hospital for mental disorders in Denmark, Finland and Sweden in 1987-2006. In each country the risk population was identified from hospital discharge registers and mortality data were retrieved from cause-of-death registers. The main outcome measure was life expectancy at age 15 years.Results: People admitted to hospital for a mental disorder had a two- to threefold higher mortality than the general population in all three countries studied. This gap in life expectancy was more pronounced for men than for women. The gap decreased between 1987 and 2006 in these countries, especially for women. The notable exception was Swedish men with mental disorders. In spite of the positive general trend, men with mental disorders still live 20 years less, and women 15 years less, than the general population.Conclusions: During the era of deinstitutionalisation the life expectancy gap for people with mental disorders has somewhat diminished in the three Nordic countries. Our results support further development of the Nordic welfare state model, i.e. tax-funded community-based public services and social protection. Health promotion actions, improved access to healthcare and prevention of suicides and violence are needed to further reduce the life expectancy gap. [ABSTRACT FROM AUTHOR]

Purpose: To compare antidepressant utilization patterns and mortality in relation to antidepressant use in men and women aged 20-34 years. Methods: We used data from the Swedish Prescribed Drug Register to identify adults aged 20-34 years who purchased at least one antidepressant in 2006. Information on death and migration was obtained from the Total Population Register by record linkage. One-year prevalence and proportion of new users, amount of purchased antidepressants, concurrent use of other antidepressants, mood stabilizers and antipsychotics and mortality were assessed. Results: The one-year prevalence of antidepressant use was 5.6% among all Swedes aged 20-34 years ( n = 94,239) and was higher among women than men (7.2 vs. 4.0%, p < 0.001). Selective serotonin reuptake inhibitors were the most dominant class of antidepressants at baseline and were more common among women than men (78.7 vs. 71.7%, p < 0.001). Of the new users, 22.3% filled only one prescription during the study period, men more often than women (24.1 vs. 21.4%, p < 0.001). The mortality rate was higher in men than in women (24 vs. 14 per 10,000, p = 0.009). Concurrent use of mood stabilizers (48 vs. 16 per 10,000, p < 0.001) and antipsychotics (50 vs. 14 per 10,000, p < 0.001) was associated with increased mortality in men and women. Conclusions: Almost twice as many Swedish women than men aged 20-34 years purchased antidepressants in 2006. Differences in utilization patterns between sexes were rather small. Discontinuation rates were high, indicating that health care providers need to acquire an increased awareness on attitudes to treatment. In both sexes, mortality rates were elevated among those concurrently using mood stabilizers and antipsychotics, which needs further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Anal sphincter rupture is a serious complication of a vaginal delivery. A considerable number of women suffer permanent anal incontinence after this type of injury. The incidence of sphincter tears is believed to have increased over several decades in Denmark, Norway, Sweden and Finland, but there seem to be significant differences in the incidence rates among these countries. The aim of this study is to compare frequency of anal sphincter tears among the four Nordic countries, and to discuss the possible reasons for the development. Study design: Ecological register study. Anal sphincter ruptures are registered as third and fourth degree perineal tears in the national birth and hospital registries in the Nordic countries. Data from these registries were sampled from Denmark, Finland, Norway and Sweden. The incidences of anal sphincter ruptures were calculated as percentages of all vaginal deliveries and caesarean sections were excluded. The test of relative proportions, Chi-square and linear regression modelling were used to study the difference between countries and time trends. Results: The frequency of anal sphincter rupture was significantly higher in three countries, Denmark 3.6%, Norway 4.1% and Sweden 4.2%, compared to Finland 0.6%. The trend was clearly increasing from the early 1970s in all countries. Conclusions: There is a significant difference in the Nordic countries in the incidence of anal sphincter tears and a significant increment in the incidence over three decades. Our hypothesis is that change in the routines during labour may be one reason for this increment. Higher episiotomy frequency in Finland may be one contributing reason. We assume that there has been a change in the conduct of labour during the last decades, and protecting the perineum may have lost its importance in the three Nordic countries, while the classic method of protecting perineum is still in use in Finland. [Copyright &y& Elsevier]

During the 1980s and 1990s, there were large social and structural changes within the Nordic countries. Here we examine time changes in risks of preterm birth by maternal educational attainment in Denmark, Finland, Norway and Sweden. Information on gestational age and maternal socio-economic position was obtained from the NorCHASE database, which includes comparable population-based register data of births from Denmark, Finland, Sweden and Norway from 1981 to 2000. The risks of very preterm birth (<32 gestational weeks) and moderately preterm birth (32–36 gestational weeks) were calculated by maternal educational attainment and analysed in 5-year intervals from 1981 to 2000. Compared with mothers with >12 years of education, mothers with <10 years of education had similarly increased risks of very, and to a lesser extent moderately, preterm birth in all four countries. The educational gradient increased slightly over time in very preterm births in Denmark, while there was a slight narrowing of the gap in Sweden. In moderately preterm births, the educational inequality gap was constant over the study period in Denmark, Norway and Sweden, but narrowed in Finland. The educational gradient in preterm birth remained broadly stable from 1981 to 2000 in all four countries. Consequently, the socio-economic inequalities in preterm birth were not strongly influenced by structural changes during the period. [ABSTRACT FROM AUTHOR]

Several studies have reported poorer infant outcome among immigrants, but contrary evidence also exists. Between 1940 and 1999 more than a half million Finns emigrated to Sweden, which made Finns the largest minority group in Sweden. Our aim was to investigate fertility trends, parturients’ background and pregnancy outcomes among Finns in Sweden, and to compare the findings with those obtained among Swedes in Sweden and Finns in Finland. The data came from the Finnish and Swedish Medical Birth Registers for the years 1987–1998. All deliveries by women born in Finland and having given birth in Sweden (N=33 874) were compared with a 10% sample of all deliveries by Swedish parturients in Sweden (N=108 549) and of all Finnish deliveries (n=75 133). Among Finns in Sweden, the number of live births per 1000 women aged 15–49 years declined significantly in the late 1990s. The change in the total fertility rate was less dramatic: the rate for Finns in Sweden followed the total Swedish rate although it remained from 5% to 10% higher up to the mid-1990s. Finns who had given birth in Sweden were older, had a higher parity and a higher prevalence of previous miscarriages, and smoked more often than did Swedes in Sweden or Finns in Finland. The crude infant outcomes of Finns having given birth in Sweden were equal to those among Swedes in Sweden (except for the incidence of small for gestational age), but poorer than in Finland. Biological factors explained the differences between Finns in Sweden and Finland in being small for gestational age, and biological factors and smoking explained the difference in prematurity. The difference in low birth weight remained statistically significant (3.9% versus 3.6% among singletons). In conclusion, fertility trends followed the pattern prevailing in the resident country. The relatively good outcome of children whose mothers were born in Finland but who had given birth in Sweden can partly be explained by the healthy migrant effect. [Copyright &y& Elsevier]

To investigate whether the risk of major congenital malformations is higher in live-born singletons conceived with intracytoplasmic sperm injection (ICSI) compared with in vitro fertilization (IVF)? Nordic register-based cohort study. Cross-linked data from Medical Birth Registers and National ART and Patient Registers in Denmark, Norway and Sweden. Data were included from the year the first child conceived using ICSI was born: Sweden, 1992; Denmark, 1994; and Norway, 1996. Data were included until 2014 for Denmark and 2015 for Norway and Sweden. All live-born singletons conceived using fresh ICSI (n = 32,484); fresh IVF (n = 47,178); without medical assistance (n = 4,804,844); and cryo-ICSI (n = 7,200) during the study period. Different in vitro conception methods, and cryopreservation of embryos. Risk of major congenital malformations on the basis of International Classification of Diseases codes. The European Concerted Action on Congenital Anomalies and Twins was used to differentiate between major and minor malformations. Among singletons conceived using fresh ICSI, 6.0% had a major malformation, compared with 5.3% of children conceived using fresh IVF; 4.2% of children conceived without medical assistance; and 4.9% of children conceived using cryo-ICSI; adjusted odds ratio (AOR) 1.07 (95% confidence interval [CI] 1.01–1.14) in ICSI vs. IVF; and AOR 1.28 (95% CI, 1.23–1.35) in ICSI vs. no medical assistance; and AOR 1.11 (95% CI, 0.99–1.26) in ICSI fresh vs. cryo-ICSI. When malformations were grouped by different organ systems, children conceived using ICSI had a higher risk of respiratory and chromosomal malformations compared with children conceived using IVF, but there were very few cases in each group. When categorizing children conceived using ICSI according to treatment indication (male factor infertility only vs. other indications), we found a higher risk of hypospadias when ICSI was performed because of male factor infertility only (AOR 1.85 [95% CI 1.03–332]). The indications for ICSI changed over time, as male factor infertility did not remain the primary indication for ICSI throughout the study period. In this large cohort study, we found the risk of major malformations in live-born singletons to be slightly higher after fresh ICSI compared with fresh IVF. These findings should be considered when choosing the assisted reproductive technology method for couples without male factor infertility. [ABSTRACT FROM AUTHOR]

To investigate whether risks of stillbirth and neonatal death differ after fresh embryo transfers (fresh-ETs) and frozen embryo transfers (frozen-ETs) compared with singletons conceived without medical assistance. A population-based cohort study. Not applicable. Data linkage between the nationwide Medical Birth Registries in Denmark (1994–2014), Norway and Sweden (1988–2015), and national quality registries and databases on assisted reproductive technology identified a total of 4,590,853 singletons, including 78,642 conceived by fresh-ET and 18,084 by frozen-ET. None Stillbirth (fetal death before and during delivery) and neonatal death (live born with death 0–27 days postpartum). Overall, 17,123 (0.37%) singletons were stillborn and 7,685 (0.17%) died neonatally. Compared with singletons conceived without medical assistance, the odds of stillbirth were similar after fresh-ET and frozen-ET, whereas the odds of neonatal death were high after fresh-ET (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.46–1.95) and frozen-ET (OR, 1.51; 95% CI, 1.08–2.10). Preterm birth (<37 gestational weeks) was more common after fresh-ET (8.0%) and frozen-ET (6.6%) compared with singletons conceived without medical assistance (5.0%), and strongly associated with neonatal mortality across all conception methods. Within gestational age categories, risk of stillbirth and neonatal death was similar for all conception methods, except that singletons from fresh-ET had a higher risk of stillbirth during gestational week 22–27 (OR, 1.85; 95% CI, 1.51–2.26). Overall, the risk of stillbirth was similar after fresh-ET and frozen-ET compared with singletons conceived without medical assistance, whereas neonatal mortality was high, possibly mediated by the high risk of preterm birth when compared with singletons conceived without medical assistance. Our results gave no clear support for choosing one treatment over the other. [ABSTRACT FROM AUTHOR]

The article presents a population based cohort study from five Nordic countries regarding the increase risk of persistent pulmonary hypertension of the newborn (PPHN) in the maternal use of selective serotonin reuptake inhibitors (SSRIs). The study has identified 30, 115 infants of mothers who had taken SSRIs during pregnancy and 1, 588, 140 infant of mothers who had not taken SSRIs. The study has found that the use of SSRIs during late pregnancy increased the risks of PPHN from 1.2 per 1000 liveborn infants to three per 1000.

Aim: To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents.Methods: Individually linked health data in Denmark (2000-2012), Finland (2005-2014), Iceland (2004-2017), Norway (2005-2015), Sweden (2006-2015), Germany (2006-2015), Australia (New South Wales, 2004-2012), Hong Kong (2001-2015), UK (2006-2016), and the US (Medicaid, 2000-2013, and IBM MarketScan, 2012-2015) were used. Using a uniformed approach, we estimated the prevalence of antipsychotic use as the proportion of pregnancies where a woman filled at least one antipsychotic prescription within three months before pregnancy until birth. For the Nordic countries, data were meta-analyzed to investigate maternal characteristics associated with the use of antipsychotics.Results: We included 8,394,343 pregnancies. Typical antipsychotic use was highest in the UK (4.4%) whereas atypical antipsychotic use was highest in the US Medicaid (1.5%). Atypical antipsychotic use increased over time in most populations, reaching 2% in Australia (2012) and US Medicaid (2013). In most countries, prochlorperazine was the most commonly used typical antipsychotic and quetiapine the most commonly used atypical antipsychotic. Use of antipsychotics decreased across the trimesters of pregnancy in all populations except Finland. Antipsychotic use was elevated among smokers and those with parity ≥4 in the Nordic countries.Conclusion: Antipsychotic use during pregnancy varied considerably between populations, partly explained by varying use of the typical antipsychotic prochlorperazine, which is often used for nausea and vomiting in early pregnancy. Increasing usage of atypical antipsychotics among pregnant women reflects the pattern that was previously reported for the general population. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To explore international differences in the classification of births at extremely low gestation and the subsequent impact on the calculation of survival rates. METHODS: We used national data on births at 22 to 25 weeks' gestation from the United States (2014; n = 11 144), Canada (2009-2014; n = 5668), the United Kingdom (2014-2015; n = 2992), Norway (2010-2014; n = 409), Finland (2010-2015; n = 348), Sweden (2011-2014; n = 489), and Japan (2014-2015; n = 2288) to compare neonatal survival rates using different denominators: all births, births alive at the onset of labor, live births, live births surviving to 1 hour, and live births surviving to 24 hours. RESULTS: For births at 22 weeks' gestation, neonatal survival rates for which we used live births as the denominator varied from 3.7% to 56.7% among the 7 countries. This variation decreased when the denominator was changed to include stillbirths (ie, all births [1.8%- 22.3%] and fetuses alive at the onset of labor [3.7%-38.2%]) or exclude early deaths and limited to births surviving at least 12 hours (50.0%-77.8%). Similar trends were seen for infants born at 23 weeks' gestation. Variation diminished considerably at 24 and 25 weeks' gestation. CONCLUSIONS: International variation in neonatal survival rates at 22 to 23 weeks' gestation diminished considerably when including stillbirths in the denominator, revealing the variation arises in part from differences in the proportion of births reported as live births, which itself is closely connected to the provision of active care. [ABSTRACT FROM AUTHOR]

Objective: To estimate the ability of an intensive interventional program to decrease the number of obstetric anal sphincter injuries (OASIS), while simultaneously decreasing the rate of Caesarean sections (CS).Study Design: The intervention, which aimed at decreasing the number of OASIS, started with a compulsory tutorial for all the midwives and physicians. At the same time, the clinic initiated a program to decrease the number of CS. We compared the outcomes before and after the intervention by calculating the risk ratios with 95% confidence intervals. The changes in selected outcomes were also tested using the test of relative proportions. The follow-up was extended for 1 year after the intervention.Results: The number of deliveries by CS decreased significantly, as did the number of OASIS in all the subgroups, except for the multi-parous women. The rate of OASIS for instrumental deliveries (mostly by vacuum) decreased significantly (p < 0.003), as compared to pre-interventional period. The number of Grade 4 tears decreased significantly: from 0.4 ruptures per 100 deliveries before the start of the intervention to 0.1 ruptures after the start of the intervention (RR 0.37, 95% CI 0.14-0.98, p = 0.037). However, the OASIS and Grade 4 sphincter injuries increased with forceps delivery. The CS rate decreased from 17.7 to 15.0 per 100 deliveries (RR 0.85, 95% CI 0.78-0.93). The post-interventional follow-up period revealed a further decrease in the frequency of OASIS (to 1.28%, p < 0.001) and a stable CS rate (14.2%).Conclusion: The intervention significantly decreases the frequency of OASIS, in line with the results obtained for earlier interventions. At the same time, a decrease in CS rate was obtained. [ABSTRACT FROM AUTHOR]

Purpose: To present the main findings of a post-authorization safety study assessing pregnancy and infant outcomes after prenatal golimumab exposure in a real-world setting., Methods: This observational population-based cohort study included data from pregnancies ending in 2006-2018 (Finland) or 2019 (Denmark, Sweden). Infants born to women with rheumatic diseases or ulcerative colitis diagnoses were identified. Based on prescription fills from 90 days prior to pregnancy until delivery, infants were assigned to one of the four drug-exposure cohorts: golimumab, other anti-TNF biologics, other biologics, and nonbiologic systemic therapy, and the general population. Prevalence of adverse pregnancy outcomes, mortality, diagnoses of major congenital anomalies (MCA), and inpatient infections in the infants' first year of life were assessed. Odds ratios and 95% CIs were calculated for MCA and infection., Results: Among 134 infants in the golimumab cohort, none were stillborn or died in the first year of life. MCA were diagnosed in 4.5% of the infants in the golimumab cohort, versus 6.8%, 10.9%, 5.5%, and 4.6% in the other anti-TNF biologics, other biologics, nonbiologic systemic therapy and general population cohorts, respectively. Inpatient infections were diagnosed in 11% of golimumab-exposed infants, compared with 9%-11% of infants in the other cohorts. Unadjusted and selected adjusted comparisons showed no association between prenatal golimumab exposure and MCA or infection compared with the other exposure cohorts or general population., Conclusions: The number of infants with prenatal golimumab exposure was low, but results are reassuringly consistent with the evidence available for other anti-TNF biologics. Continued monitoring is needed., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aims/hypothesis: Children and adults born preterm have an increased risk of type 1 diabetes. However, there is limited information on risk patterns across the full range of gestational ages, especially after extremely preterm birth (23-27 weeks of gestation). We investigated the risk of type 1 diabetes in childhood and young adulthood across the full range of length of gestation at birth., Methods: Data were obtained from national registers in Finland, Norway and Sweden. In each country, information on study participants and gestational age was collected from the Medical Birth Registers, information on type 1 diabetes diagnoses was collected from the National Patient Registers, and information on education, emigration and death was collected from the respective national register sources. Individual-level data were linked using unique personal identity codes. The study population included all individuals born alive between 1987 and 2016 to mothers whose country of birth was the respective Nordic country. Individuals were followed until diagnosis of type 1 diabetes, death, emigration or end of follow-up (31 December 2016 in Finland, 31 December 2017 in Norway and Sweden). Gestational age was categorised as extremely preterm (23-27 completed weeks), very preterm (28-31 weeks), moderately preterm (32-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks; reference) and post term (42-45 weeks). HRs and 95% CIs from country-specific covariate-adjusted Cox regression models were combined in a meta-analysis using a common-effect inverse-variance model., Results: Among 5,501,276 individuals, 0.2% were born extremely preterm, 0.5% very preterm, 0.7% moderately preterm, 4.2% late preterm, 17.7% early term, 69.9% full term, and 6.7% post term. A type 1 diabetes diagnosis was recorded in 12,326 (0.8%), 6364 (0.5%) and 16,856 (0.7%) individuals at a median age of 8.2, 13.0 and 10.5 years in Finland, Norway and Sweden, respectively. Individuals born late preterm or early term had an increased risk of type 1 diabetes compared with their full-term-born peers (pooled, multiple confounder-adjusted HR 1.12, 95% CI 1.07, 1.18; and 1.15, 95% CI 1.11, 1.18, respectively). However, those born extremely preterm or very preterm had a decreased risk of type 1 diabetes (adjusted HR 0.63, 95% CI 0.45, 0.88; and 0.78, 95% CI 0.67, 0.92, respectively). These associations were similar across all three countries., Conclusions/interpretation: Individuals born late preterm and early term have an increased risk of type 1 diabetes while individuals born extremely preterm or very preterm have a decreased risk of type 1 diabetes compared with those born full term., (© 2024. The Author(s).)

Background: Growing up with parental alcohol use disorder (AUD) is a risk factor for psychiatric disorders. This study investigated the risk of mood disorders and of anxiety disorders in the adult children of parents with AUD, adjusted for sociodemographic factors., Methods: Individual-level register data on the total population were linked to follow children of parents with AUD from 1973 to 2018 to assess their risk of mood disorders and of anxiety disorders. AUD, mood disorders and anxiety disorders were defined with International Statistical Classification of Diseases and Related Health Problems codes from the National Patient Register. HRs of outcomes were calculated with Cox regression. Model 1 was adjusted for the child's sex, parental education and death of a parent. Model 2 was adjusted for those factors and parental diagnosis of mood or anxiety disorder., Results: Those with ≥1 parent with AUD (99 723 of 2 421 479 children) had a higher risk of mood disorder and of anxiety disorder than those whose parents did not have AUD (HR mood 2.32, 95% CI 2.26 to 2.39; HR anxiety 2.66, 95% CI 2.60 to 2.72). The risk remained elevated after adjustment for sociodemographic factors and parental psychiatric diagnosis (HR mood 1.67, 95% CI 1.63 to 1.72; HR anxiety 1.74, 95% CI 1.69 to 1.78). The highest risks were associated with AUD in both parents, followed by AUD in mothers and then in fathers., Conclusion: Adult children of parents with AUD have a raised risk of mood and anxiety disorders even after adjustment for sociodemographic factors and parental mood or anxiety disorder. These population-level findings can inform future policies and interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Uterine sarcomas are a rare group of uterine malignancies. Due to the low incidence and changes in uterine sarcoma classification, risk factors are not well characterized. Our objective was to evaluate risk factors for uterine sarcoma and compare risk factors between uterine sarcoma, malignant mixed Mullerian tumors (MMMTs), and type I endometrial carcinomas., Methods: This nested case-control study utilized linked data from population-based medical birth and cancer registries in Denmark, Finland, Norway, and Sweden. Up to 10 controls were matched on country and birth year for each uterine cancer case. Using multivariable adjusted multinomial logistic regression, estimates of the associations between pregnancy-related factors and risk of uterine sarcoma, MMMTs, and type I endometrial carcinomas were determined., Results: Having a very-low-birth-weight infant (< 1500 vs. 2500-3999 g: OR [95% CI] 2.83 [1.61-4.96]) was associated with an increased risk of uterine sarcoma. Whereas, having a more recent pregnancy was associated with reduced risks of MMMT (< 10 vs. ≥ 30 years: 0.66 [0.20-2.23]) and type 1 endometrial carcinomas (0.35 [0.30-0.41]) but not uterine sarcomas (1.33 [0.90-1.98], p-heterogeneity < 0.01)., Conclusion: Our study provides evidence that risk factors for uterine sarcoma and MMMT, previously grouped with uterine sarcomas, vary substantially. Additionally, MMMT and type I endometrial carcinomas are more similar than uterine sarcoma in that pregnancy complications like gestational hypertension and preeclampsia were associated with reduced risks of both but not uterine sarcoma, suggesting different etiologies., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The percentage of people without children over their lifetime is approximately 25% in men and 20% in women. Individual diseases have been linked to childlessness, mostly in women, yet we lack a comprehensive picture of the effect of early-life diseases on lifetime childlessness. We examined all individuals born in 1956-1968 (men) and 1956-1973 (women) in Finland (n = 1,035,928) and Sweden (n = 1,509,092) to the completion of their reproductive lifespan in 2018. Leveraging nationwide registers, we associated sociodemographic and reproductive information with 414 diseases across 16 categories, using a population and matched-pair case-control design of siblings discordant for childlessness (71,524 full sisters and 77,622 full brothers). The strongest associations were mental-behavioural disorders (particularly among men), congenital anomalies and endocrine-nutritional-metabolic disorders (strongest among women). We identified new associations for inflammatory and autoimmune diseases. Associations were dependent on age at onset and mediated by singlehood and education. This evidence can be used to understand how disease contributes to involuntary childlessness., (© 2023. The Author(s).)

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

Study Question: Is transfer of vitrified blastocysts associated with higher perinatal and maternal risks compared with slow-frozen cleavage stage embryos and fresh blastocysts?, Summary Answer: Transfer of vitrified blastocysts is associated with a higher risk of preterm birth (PTB) when compared with slow-frozen cleavage stage embryos and with a higher risk of a large baby, hypertensive disorders in pregnancy (HDPs) and postpartum hemorrhage (PPH) but a lower risk of placenta previa when compared with fresh blastocysts., What Is Known Already: Transfer of frozen-thawed embryos (FETs) plays a central role in modern fertility treatment, limiting the risk of ovarian hyperstimulation syndrome and multiple pregnancies. Following FET, several studies report a lower risk of PTB, low birth weight (LBW) and small for gestational age (SGA) yet a higher risk of fetal macrosomia and large for gestational age (LGA) compared with fresh embryos. In recent years, the introduction of new freezing techniques has increased treatment success. The slow-freeze technique combined with cleavage stage transfer has been replaced by vitrification and blastocyst transfer. Only few studies have compared perinatal and maternal outcomes after vitrification and slow-freeze and mainly in cleavage stage embryos, with most studies indicating similar outcomes in the two groups. Studies on perinatal and maternal outcomes following vitrified blastocysts are limited., Study Design, Size, Duration: This registry-based cohort study includes singletons born after frozen-thawed and fresh transfers following the introduction of vitrification in Sweden and Denmark, in 2002 and 2009, respectively. The study includes 3650 children born after transfer of vitrified blastocysts, 8123 children born after transfer of slow-frozen cleavage stage embryos and 4469 children born after transfer of fresh blastocysts during 2002-2015. Perinatal and maternal outcomes in singletons born after vitrified blastocyst transfer were compared with singletons born after slow-frozen cleavage stage transfer and singletons born after fresh blastocyst transfer. Main outcomes included PTB, LBW, macrosomia, HDP and placenta previa., Participants/materials, Setting, Methods: Data were obtained from the CoNARTaS (Committee of Nordic ART and Safety) group. Based on national registries in Sweden, Finland, Denmark and Norway, the CoNARTaS cohort includes all children born after ART treatment in public and private clinics 1984-2015. Outcomes were assessed with logistic multivariable regression analysis, adjusting for the country and year of birth, maternal age, body mass index, parity, smoking, parental educational level, fertilisation method (IVF/ICSI), single embryo transfer, number of gestational sacs and the child's sex., Main Results and the Role of Chance: A higher risk of PTB (<37 weeks) was noted in the vitrified blastocyst group compared with the slow-frozen cleavage stage group (adjusted odds ratio, aOR [95% CI], 1.33 [1.09-1.62]). No significant differences were observed for LBW (<2500 g), SGA, macrosomia (≥4500 g) and LGA when comparing the vitrified blastocyst with the slow-frozen cleavage stage group. For maternal outcomes, no significant difference was seen in the risk of HDP, placenta previa, placental abruption and PPH in the vitrified blastocyst versus the slow frozen cleavage stage group, although the precision was limited.When comparing vitrified and fresh blastocysts, we found higher risks of macrosomia (≥4500 g) aOR 1.77 [1.35-2.31] and LGA aOR 1.48 [1.18-1.84]. Further, the risks of HDP aOR 1.47 [1.19-1.81] and PPH aOR 1.68 [1.39-2.03] were higher in singletons born after vitrified compared with fresh blastocyst transfer while the risks of SGA aOR 0.58 [0.44-0.78] and placenta previa aOR 0.35 [0.25-0.48] were lower., Limitations, Reasons for Caution: Since vitrification was introduced simultaneously with blastocyst transfer in Sweden and Denmark, it was not possible to explore the effect of vitrification per se in this study., Wider Implications of the Findings: The results from the change of strategy to vitrification of blastocysts are reassuring, indicating that the freezing technique per se has no major influence on the perinatal and maternal outcomes. The higher risk of PTB may be related to the extended embryo culture rather than vitrification., Study Funding/competing Interest(s): The study is part of the ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. The study was also financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation and NordForsk (project 71 450). There are no conflicts of interest to declare., Trial Registration Number: ISRCTN11780826., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Low Apgar score has been associated with higher risk for several neurological and psychiatric disorders, including cerebral palsy and intellectual disability. Studies of the association between Apgar score and autism spectrum disorder (ASD) have been inconsistent. We aimed to investigate (1) the association between low Apgar score at 5 min and risk for ASD, and (2) the modifying effects of gestational age and sex on this association in the largest multinational database of ASD. We included prospective data from 5.5 million individuals and over 33,000 cases of ASD from Norway, Sweden, Denmark and Western Australia who were born between 1984 and 2007. We calculated crude and adjusted risk ratios (RR) with 95% confidence intervals (95% CIs) for the associations between low Apgar score and ASD. All analyses for ASD were repeated for autistic disorder (AD). We used interaction terms and stratified analysis to investigate the effects of sex, gestational age, and birth weight on the association. In fully adjusted models, low Apgar scores (1-3) (RR, 1.42; 95% CI, 1.16-1.74), and intermediate Apgar scores (4-6) (RR, 1.50; 95% CI, 1.36-1.65) were associated with a higher RR of ASD than optimal Apgar score (7-10). The point estimates for low (RR, 1.88; 95% CI, 1.41-2.51) and intermediate Apgar score (RR, 1.54; 95% CI, 1.32-1.81) were larger for AD than for ASD. This study suggests that low Apgar score is associated with higher risk of ASD, and in particular AD. We did not observe any major modifying effects of gestational age and sex, although there seems to be substantial confounding by gestational age and birth weight on the observed association.

Objectives: This study aims to estimate the association between pregnancy-associated maternal cancers, diagnosed both prenatally and postnatally, and birth outcomes., Design: Population-based register study., Setting: National registers of Denmark and Sweden., Participants: A total of 5 523 365 children born in Denmark (1977-2008) and Sweden (1973-2006).Primary and secondary outcome measures: gestational age, birth weight, size for gestational age, Apgar score, caesarean section and sex were the outcomes of interest. ORs and relative risk ratios (RRR) with 95% CIs were estimated using logistic regression and multinomial logistic regression, respectively., Results: In this study, 2% of children were born to mothers with a diagnosis of cancer. Children whose mothers received a prenatal cancer diagnosis had higher risk of being born preterm (RRR: 1.77, 95% CI 1.64 to 1.90); low birth weight (RRR 1.84, 95% CI 1.69 to 2.01); low Apgar score (OR 1.36, 95% CI 1.20 to 1.56); and by caesarean section (OR: 1.69, 95% CI 1.59 to 1.80). Associations moved towards the null for analyses using postnatal diagnoses, but preterm birth (RRR: 1.13, 95% CI 1.09 to 1.17) and low birth weight (RRR: 1.14, 95% CI 1.09 to 1.18) remained statistically significant, while risk of caesarean section became so (OR: 0.95, 95% CI 0.91 to 0.98). Additionally, statistical significance was reached for large for gestational age (RRR: 1.06, 95% CI 1.01 to 1.11), high birth weight (RRR: 1.04, 95% CI 1.01 to 1.06) and caesarean section (OR: 0.95, 95% CI 0.91 to 0.98)., Conclusions: Results suggest an association between pregnancy-associated cancers and adverse birth outcomes in the offspring. While this is strongest for prenatally diagnosed cancers, some smaller associations exist for postnatally diagnosed cancers, indicating that cancer itself could affect fetal development, or that cancer and adverse birth outcomes share risk factors. Future studies on maternal cancer during pregnancy should consider including some postnatal years in their exposure window., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Epithelial ovarian cancer is a fatal disease of largely unknown etiology. Higher parity is associated with reduced risk of ovarian cancer. However, among parous women, the impact of pregnancy-related factors on risk is not well understood. This population-based case-control study included all parous women with epithelial ovarian cancer in Denmark, Finland, Norway and Sweden during 1967-2013 (n = 10,957) and up to 10 matched controls (n = 107,864). We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for pregnancy-related factors and ovarian cancer risk by histological subtype. Preterm delivery was associated with an increased risk [pregnancy length (last pregnancy) ≤30 vs. 39-41 weeks, OR 1.33 (95% CI 1.06-1.67), adjusted for number of births]; the OR increased as pregnancy length decreased (p for trend < 0.001). Older age at first and last birth was associated with a decreased risk [first birth: 30-39 vs. <25 years: adjusted OR 0.76 (95% CI 0.70-0.83); last birth 30-39 vs. <25 years: adjusted OR 0.76 (95% CI 0.71-0.82)]. Increasing number of births was protective [≥4 births vs. 1; OR 0.63 (95% CI 0.59-0.68)] for all subtypes, most pronounced for clear-cell tumors [OR 0.30, (95% CI 0.21-0.44), p heterogeneity  < 0.001]. No associations were observed for multiple pregnancies, preeclampsia or offspring size. In conclusion, in addition to high parity, full-term pregnancies and pregnancies at older ages were associated with decreased risk of ovarian cancer. Our findings favor the cell clearance hypothesis, i.e. a recent pregnancy provides protection by clearing of precancerous cells from the epithelium of the ovary/fallopian tubes, mediated by placental or ovarian hormones., (© 2018 UICC.)

Certain features of pregnancy are important risk factors for breast cancer, such as protection afforded by young age at first birth. Preeclampsia, a pregnancy complication, is associated with reduced maternal breast cancer risk. However, questions remain regarding causality, biological mechanisms and the relation of other hypertensive conditions to risk. We conducted a population-based case-control study of breast cancer cases (n = 116,196) in parous women identified through linkage of birth and cancer registries in Denmark, Finland, Norway and Sweden (1967-2013), including up to 10 matched controls per case (n = 1,147,192) sampled from the birth registries (complete data were not available on all variables). Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models including matching factors (country, maternal birth year) and parity. Hypertension diagnosed before pregnancy (OR 0.87; 95% CI 0.78-0.97), gestational hypertension (OR 0.90; 95% CI 0.86-0.93) and preeclampsia (OR 0.91; 95% CI 0.88-0.95) were associated with reduced breast cancer risk. Results remained similar after adjustment for smoking and maternal body mass index before first pregnancy, and were generally similar stratified by parity, age at breast cancer diagnosis, time since first and last birth, sex of the offspring and calendar time. Except for retained placenta (OR 1.14; 95% CI 0.98-1.32), no other pregnancy complication appeared associated with breast cancer risk. The mechanisms mediating the modest risk reductions for history of preeclampsia or hypertension preceding or arising during pregnancy, and possible increased risk with history of retained placenta are unknown and warrant further laboratory, clinical and epidemiological investigation., (© 2018 UICC.)

Introduction: Children born after assisted reproductive technology, particularly singletons, have been shown to have an increased risk of congenital malformations compared with children born after spontaneous conception. We wished to study whether there has been a change in the past 20 years in the risk of major congenital malformations in children conceived after assisted reproductive technology compared with children spontaneously conceived., Material and Methods: Population-based cohort study including 90 201 assisted reproductive technology children and 482 552 children spontaneously conceived, born in Denmark, Finland, Norway and Sweden. Both singletons and twins born after in vitro fertilization, intracytoplasmatic sperm injection and frozen embryo transfer were included. Data on children were taken from when the national Nordic assisted reproductive technology registries were established until 2007. Multiple logistic regression analyses were used to estimate the risks and adjusted odds ratios for congenital malformations in four time periods: 1988-1992, 1993-1997, 1998-2002 and 2003-2007. Only major malformations were included., Results: The absolute risk for singletons of being born with a major malformation was 3.4% among assisted reproductive technology children vs. 2.9% among children spontaneously conceived during the study period. The relative risk of being born with a major congenital malformation between all assisted reproductive technology children and children spontaneously conceived remained similar through all four time periods (p = 0.39). However, we found that over time the number of children diagnosed with a major malformation increased in both groups across all four time periods., Conclusion: When comparing children conceived after assisted reproductive technology and spontaneously conceived, the relative risk of being born with a major congenital malformation did not change during the study period., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Purpose: A history of anorexia nervosa has been associated with a reduced risk of developing breast cancer. We investigated survival after breast cancer among women with a prior anorexia nervosa diagnosis compared with women in a population comparison group., Methods: This register-based study included combined data from Sweden, Denmark and Finland. A total of 76 and 1462 breast cancer cases identified among 22,654 women with anorexia nervosa and 224,619 women in a population comparison group, respectively, were included in the study. Hazard ratios (HR) for overall and breast cancer-specific mortality after breast cancer diagnosis were estimated using Cox regression. Cause of death was available only for Swedish and Danish women; therefore, the analysis on breast cancer-specific mortality was restricted to these women., Results: We observed 23 deaths after breast cancer among anorexia nervosa patients and 247 among population comparisons. The overall mortality after the breast cancer diagnosis was increased in women with a history of anorexia nervosa compared with population comparisons (HR 2.5, 95% CI 1.6-3.9) after adjustment for age, period and extent of disease. Results were similar for overall (HR 2.3, 95% CI 1.4-3.6) and breast cancer-specific mortality (HR 2.1, 95% CI 1.3-3.6) among Swedish and Danish women., Conclusions: We found that female breast cancer patients with a prior diagnosis of anorexia nervosa have a worse survival compared with other breast cancer patients.

Background: Mortality in children under five years has been widely studied, whereas mortality at 5-9 years has received little attention. Using unique data from national registers in three Nordic countries, we aimed to characterize mortality directionality in children aged 0 to 9 years., Methods and Findings: The cohort study included all children born in Denmark from 1973 to 2008 (n = 2,433,758), Sweden from 1973 to 2006 (n = 3,400,212), and a random sample of 89.3% of children born in Finland from 1987 to 2007 (n = 1,272,083). Children were followed from 0 to 9 years, and cumulative mortality and mortality rates were compared by age, gender, cause of death, and calendar periods. Among the 7,105,962 children, there were 48,299 deaths during study period. From 1981-1985 to 2001-2005, all-cause mortality rates were reduced by between 34% and 62% at different ages. Overall mortality rate ratio between boys and girls decreased from 1.25 to 1.21 with the most prominent reduction in children aged 5-9 years (from 1.59 to 1.19). Neoplasms, diseases of the nervous system and transport accidents were the most frequent cause of death after the first year of life. These three leading causes of death declined by 42% (from 6.2 to 3.6 per 100,000 person years), 43% (from 3.7 to 2.1) and 62% (from 3.9 to 1.5) in boys, and 25% (from 4.1 to 3.1 per 100000 person years), 42% (from 3.4 to 1.9) and 63% (from 3.0 to 1.1) in girls, respectively. Mortality from neoplasms was the highest in each age except infants when comparing cause-specific mortality, and half of deaths from diseases of the nervous system occurred in infancy. Mortality rate due to transport accidents increased with age and was highest in boys aged 5-9 years., Conclusions: Mortality rate in children aged 0-9 years has been decreasing with diminished difference between genders over the past decades. Our results suggest the importance of further research on mortality by causes of neoplasms, and causes of transport accidents-especially in children aged 5-9 years.

We aimed to examine whether early life bereavement, as indicator of severe stress, was associated with an increased risk of schizophrenia later in life.Based on population registers, we established a cohort of all children born in Denmark (N = 1 686 416) and Sweden (N = 2 563 659) from 1973 to 1997. Children were categorized as exposed if they lost a first-degree relative during the first 18 years of life. Outcome is the first diagnosis of schizophrenia as either inpatient or outpatient. Log-linear Poisson regression models were used to estimate incidence rate ratios (IRRs).A total of 188,850 children (4.6%) experienced death of a first-degree relative from birth to 18 years of age. Compared with unexposed children, those exposed had overall a 39% higher risk of schizophrenia (= 1.39, 95% CI [confidence interval]: 1.32-1.47). The IRR was particularly high if the family member committed suicide (aIRR = 2.11, 95% CI: 1.90-2.34) or died due to an injury or accident (aIRR = 1.44, 95% CI: 1.27-1.63). The IRR of schizophrenia decreased with increasing child's age at bereavement (P < 0.0001). Children who experienced >1 death during the first 18 years of life (aIRR = 1.79, 95% CI: 1.46-2.19) had a higher risk than those with a single death (aIRR = 1.37, 95% CI: 1.30-1.45).The study suggested that exposure to death of a first-degree relative before 18 years was associated with an increased risk of schizophrenia in later life. The complex mechanisms behind these associations remain to be elucidated., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Up to one-third of women receive prescriptions for systemic antibacterial medications during pregnancy. This paper looks at the association between maternal use of systemic antibacterial medications during pregnancy and childhood cancer risk in the offspring using the prospective data on medication., Methods: A population-based follow-up study was carried out using Danish and Swedish register data. Exposure was maternal redemption of a prescription for a systemic antibacterial in the 3 months prior to pregnancy and during pregnancy (exposure window) documented in the national prescription registers, and offspring were followed up from birth to a cancer diagnosis, death, emigration, day before 15th birthday or end of follow-up, whichever came first. Timing, dosage, specific medication types and types of childhood cancer were also considered., Results: Mothers of 35.1% (n = 506,194) of the children filled at least one prescription for systemic antibacterials during the exposure window. Exposed children had a hazard ratio of 1.08 (95% confidence interval: 0.97, 1.20) compared with unexposed children. Statistically significant results were found for some specific medications (for example, 'other antibacterials'/Anatomical Therapeutic Chemical code J01X) and combinations of cancer types and specific medications (leukaemia and other antibacterials, and hepatic cancers and tetracyclines)., Conclusions: The results of this study indicate that most antibacterial drugs used during pregnancy were not related to childhood cancer risk in the offspring. However, some may be associated with the development of some specific types of childhood cancers. Our findings need to be replicated in an independent data source., (Copyright © 2015 John Wiley & Sons, Ltd.)