Placental weight percentile curves in a Danish population.

INTRODUCTION: The role of the placenta is to transport oxygen and nutrients to the fetus, and a well-functioning placenta is vital to fetal health. Our aim was to develop placental weight percentile curves adjusted by gestational age, and stratified by major maternal comorbidities. MATERIAL AND METHODS: The study was a population study in a Danish cohort. Data was drawn from The Medical Birth Register and the National Patient Register. We included singleton births with a gestational age of 22 + 0 to 42 + 6 weeks. We excluded multiple pregnancies, stillbirths and retained placentas. A total of 611 418 placentas were included. Percentile line graphs were created in groups of all placentas, hypertensive disorders and diabetic disorders. RESULTS: Tables and figures are presented for placental weight percentile curves according to gestational age for all placentas, hypertensive disorders and diabetic disorders, respectively. Placental weight was generally higher in the diabetic placentas, and lower in the hypertensive placentas. CONCLUSIONS: These percentile curves may serve as a reference for other populations, and may be useful for other studies investigating the role of the placenta in relation to pregnancy outcomes, and health in later life.

Incidence of shoulder dystocia and risk factors for recurrence in the subsequent pregnancy-A historical register-based cohort study.

INTRODUCTION: Shoulder dystocia is a rare obstetric complication, and the risk of recurrence is important for planning future deliveries. MATERIAL AND METHODS: The objectives of our study were to estimate the incidence and risk factors for recurrence of shoulder dystocia and to identify women at high risk of recurrence in a subsequent vaginal delivery. The study design was a nationwide register-based study including data from the Danish Medical Birth Registry and National Patient Register in the period 2007-2017. Nulliparous women with a singleton fetus in cephalic presentation were included for analysis of risk factors in index and subsequent delivery. RESULTS: During the study period, 6002 cases of shoulder dystocia were reported with an overall incidence among women with vaginal delivery of 1.2%. Among 222 225 nulliparous women with vaginal births, shoulder dystocia complicated 2209 (1.0%) deliveries. A subsequent birth was registered in 1106 (50.1%) of the women with shoulder dystocia in index delivery of which 837 (77.8%) delivered vaginally. Recurrence of shoulder dystocia was reported in 60 (7.2%) with a six-fold increased risk compared with women without a prior history of shoulder dystocia (risk ratio [RR] 5.70, 95% confidence interval [CI]: 4.41 to 7.38; adjusted RR 3.06, 95% CI: 2.03 to 4.68). Low maternal height was a significant risk factor for recurrence of shoulder dystocia. In the subsequent delivery, significant risk factors for recurrence were birthweight >4000 g, positive fetal weight difference exceeding 250 g from index to subsequent delivery, stimulation with oxytocin and operative vaginal delivery. In the subsequent pregnancy following shoulder dystocia, women who underwent a planned cesarean (n = 176) were characterized by more advanced age and a higher prevalence of diabetes in the subsequent pregnancy. Furthermore, they had more often experienced operative vaginal delivery, severe perineal lacerations, and severe neonatal complications at the index delivery. CONCLUSIONS: The incidence of shoulder dystocia among nulliparous women with vaginal delivery was 1.0% with a 7.2% risk of recurrence in a population where about 50% had a subsequent birth and of these 78% had subsequent vaginal delivery. Important risk factors for recurrence were low maternal height, increase of birthweight ≥250 g from index to subsequent delivery and operative vaginal delivery.

Risk of Bowel Obstruction after Hysterectomy for Benign Indication According to Surgical Method in Denmark, 1984-2013.

STUDY OBJECTIVE: To estimate the risk of bowel obstruction (BO) after hysterectomy for benign indications depending on the surgical method (abdominal, vaginal, or laparoscopic) and identify risk factors for adhesive BO. DESIGN: A national registry-based cohort. SETTING: Danish hospitals during the period 1984-2013. PATIENTS: Danish women who underwent hysterectomy for benign indications (N = 125 568). INTERVENTIONS: Abdominal hysterectomies were compared with vaginal hysterectomies, laparoscopic hysterectomies, and minimally invasive (vaginal and laparoscopic) hysterectomies. MEASUREMENTS AND MAIN RESULTS: The incidence of BO according to the surgical method was compared using Cox proportional hazard regression. The covariates included were the time period, age, concomitant operations, previous abdominal surgery or disease, and socioeconomic factors. In a subanalysis (n = 35 712 women) of the period 2004-2013, detailed information from the Danish Hysterectomy Database enabled the inclusion of patient-, surgery-, and complication-related covariates. The overall crude incidence of BO was 17.4 of 1000 hysterectomies (2196 incident cases). The 10-year cumulative incidence of BO differed among the surgical routes (abdominal, 1.7%; laparoscopic, 1.4%; and vaginal, 0.9%). In multiple-adjusted analyses, the risk of BO was higher after abdominal hysterectomy than after vaginal (hazard ratio 1.64 [95% confidence interval, 1.39-1.93]) and minimally invasive (vaginal or laparoscopic) hysterectomy (hazard ratio 1.54 [1.33-1.79]). Additional pre-existing risk factors for BO at the time of hysterectomy were increased age, low education, low income, smoking, high American Society of Anesthesiologists comorbidity score, history of infertility, abdominal infection, and previous abdominal surgery (apart from cesarean section), penetrating lesions in abdominal organs, or operative adhesiolysis. Perioperative risk factors at the time of hysterectomy included concomitant removal of the ovaries, adhesiolysis, blood transfusion, readmission, and overall presence of perioperative complications. CONCLUSION: Abdominal hysterectomy is associated with a 54% higher risk of BO than minimally invasive (laparoscopic or vaginal) hysterectomy.

Lifetime induced abortions and live births. A 40-year historical cohort study.

OBJECTIVE: Little is known about whether induced abortions are associated with the final lifetime number of live births (life births). The objective of this study was to examine the association of number of life births with number of abortions a female has had in her lifetime. METHODS: In a national cohort design, we followed all Danish females from ages 15 to 44 years through the period 1977-2017 for induced abortions and live births. For each lifetime number of induced abortions, the average number of life births were assessed, and rates with 95% confidence limits calculated. RESULTS: The study included 409 497 females who completed 222 482 induced abortions and 831 742 live births. In 265 573 (64.9%) females who did not have any induced abortion, the average number of life births was 2.09 (95% CI 2.08-2.10). For females with 1 (23.4%), 2 (7.4%), 3 (2.6%), 4 (1.0%), and ≥5 (0.7%) induced abortions during their reproductive lifespan, the average number of life births was 1.88 (1.87-1.89), 1.99 (1.98-2.00), 2.09 (2.06-2.11), 2.13 (2.09-2.15), and 2.25 (2.21-2.29), respectively. The increase in number of life births in females with 1 to females with 5+ induced abortions was 4.7% for each additional induced abortion. CONCLUSION: We found number of induced abortions during a woman's reproductive lifespan to be positively correlated to the number of live births. This association is likely explained by a high fecundity in females with multiple pregnancies including induced abortions, and suggests that even several induced abortions do not compromise a woman's general reproductive end points.

Age-dependent influenza infection patterns and subtype circulation in Denmark, in seasons 2015/16 to 2021/22.

BackgroundInfluenza was almost absent for 2 years following the implementation of strict public health measures to prevent the spread of SARS-CoV-2. The consequence of this on infections in different age groups is not yet known.AimTo describe the age groups infected with the influenza virus in 2021/22, the first post-pandemic influenza season in Denmark, compared with the previous six seasons, and subtypes circulating therein.MethodsInfection and hospitalisation incidences per season and age group were estimated from data in Danish registries. Influenza virus subtypes and lineages were available from samples sent to the National Influenza Centre at Statens Serum Institut.ResultsTest incidence followed a similar pattern in all seasons, being highest in 0-1-year-olds and individuals over 75 years, and lowest in 7-14-year-olds and young people 15 years to late twenties. When the influenza A virus subtypes A(H3N2) and A(H1N1)pdm09 co-circulated in seasons 2015/16 and 2017/18 to 2019/20, the proportion of A(H1N1)pdm09 was higher in 0-1-year-olds and lower in the over 85-year-olds compared with the overall proportion of A(H1N1)pdm09 in these seasons. The proportion of A(H3N2) was higher in the over 85 years age group compared with the overall proportion of A(H3N2). The 2016/17 and 2021/22 seasons were dominated by A(H3N2) but differed in age-specific trends, with the over 85 years age group initiating the 2016/17 season, while the 2021/22 season was initiated by the 15-25-year-olds, followed by 7-14-year-olds.ConclusionThe 2021/22 influenza season had a different age distribution compared with pre-COVID-19 pandemic seasons.

Winter, spring, summer or fall: temporal patterns in placenta-mediated pregnancy complications-an exploratory analysis.

PURPOSE: Placenta-mediated pregnancy complications, like growth restriction and hypertensive disorders, are leading causes of maternal, fetal and neonatal morbidity and mortality in high-income countries. The purpose was to investigate if there is a seasonal variation in placenta-mediated pregnancy complications (small for gestational age, intrauterine growth restriction, preeclampsia, preterm birth and intrauterine fetal death). METHODS: This is a Danish cohort study including all singleton deliveries at gestational week 22 up to and including week 41 conceived from December 2006 to November 2016 (N = 555,459). We used statistical process control charts to visualize data and to test for patterns of non-random variation in data over time for pregnancies with risk factors (BMI, diabetes, in vitro fertilization, maternal age > 40 years, primipara, previous caesarean and smoking) and each of the following outcome: fetal growth restriction, hypertensive disorders, preterm birth and intrauterine fetal death. The study was approved by the Danish Data Protection agency; REG-039-2019. RESULTS: We found a seasonal pattern in hypertensive disorders during pregnancy with dips in pregnancies conceived in the fall season and highest risk by conception in the spring and summer season. We found no apparent seasonality in cases of preterm delivery, small for gestational age and intrauterine mortality. Individual risk factors (e.g. smoking and obesity) for placenta-mediated complicated over time were in consistency with the general trends. CONCLUSIONS: We found a significant seasonal variation in the risk of hypertensive disorders of pregnancy with highest risk by conception in the spring and summer season. This study found no seasonal variation in other placenta-mediated complications.

Incidence of postpartum hemorrhage and risk factors for recurrence in the subsequent pregnancy.

PURPOSE: To assess incidence and risk factors for postpartum hemorrhage (PPH) and identify women at high risk of recurrence in the subsequent pregnancy. METHODS: This register-based study includes data on women from the Capital Region of Denmark with two consecutive deliveries recorded in the Copenhagen Obstetric Database from 2007 to 2020. PPH, defined as a blood loss of 1000 mL or more within 24 h after delivery, was the primary outcome measure. We calculated incidence and recurrence rate of PPH and assessed possible risk factors at index and subsequent deliveries. RESULTS: We included 44,800 women with 95,673 deliveries. The overall incidence of PPH was 6.3%. Women with previous PPH had a 3.5-fold increased risk of PPH in a subsequent delivery compared to unaffected women (19.1 vs. 5.4%; OR 4.1; 95% CI 3.7-4.5). Major risk factors for recurrence were PPH in combination with blood transfusion or manual removal of placenta at the index delivery. Labor induction in subsequent pregnancy increased the risk of recurrent PPH compared to spontaneous onset (OR 1.5; 95% CI 1.2-1.9), while planned caesarean section reduced the risk, compared to planned vaginal delivery (OR 0.6; 95% CI 0.4-0.7). CONCLUSION: Previous PPH increases the risk of PPH in subsequent pregnancy 3.5-fold. The risk of recurrent PPH increases with labor induction and decreases with planned caesarean section in the subsequent pregnancy. To prevent recurrent PPH, personalized counseling based on risk factors, relevant labor history and maternal preferences is suggested.

Outcome of subsequent pregnancies in women with complete uterine rupture: A population-based case-control study.

INTRODUCTION: In the attempt of a trial of labor after a cesarean section approximately one in 200 women experience a complete uterine rupture. As a complete uterine rupture is associated with an adverse perinatal outcome, data regarding subsequent pregnancies are needed to provide proper care and guidance to women with a complete uterine rupture when informing them of future possibilities. The objective of this study was to investigate the fetal and maternal outcomes in subsequent pregnancies after a complete uterine rupture. MATERIAL AND METHODS: Retrospective population-based case-control study. Denmark 1997-2017. A total of 175 women with complete uterine rupture during an attempted trial of labor after cesarean (TOLAC) at term (cases) and a corresponding group of 272 women with no uterine rupture during an attempted TOLAC at term (controls) were labeled as index deliveries. Index deliveries were included from January 1, 1997 to December 31, 2008. From the date of the index delivery to December 31, 2017 the information on subsequent pregnancies and deliveries, and on referral to hospital with any obstetric or gynecological diagnosis were retrieved from the Danish Medical Birth Registry and National Patient Registry. Main outcome measures were miscarriage, perinatal death, neonatal morbidity, preterm birth, and recurrence of uterine rupture. Outcome measures were compared between cases and controls. RESULTS: After the index deliveries; there were 109 pregnancies and 70 deliveries after gestational age 22+0  weeks in the population of cases. In the population of controls, there were 183 pregnancies and 126 deliveries after 22+0  weeks. Cases had a significantly higher risk of miscarriage (odds ratio [OR] 3.99; 95% confidence interval [CI] 1.36-13.17). The incidence of uterine rupture was 8.6% among cases and 0.8% among controls (OR 11.7; 95% CI 1.36-543.1). Among cases, 98.6% had live-born infants, and none of these had severe neonatal morbidity. No significant association was found between previous complete uterine rupture and preterm delivery, placenta previa, hysterectomy in relation to subsequent births, diagnosis such as meno/metrorrhagia, dysmenorrhea, or procedures such as hysteroscopy or hysterectomy. CONCLUSIONS: In pregnancies following complete uterine rupture continuing after 22+0  weeks, maternal and fetal outcomes are good when managed promptly with cesarean delivery.

Gender incongruence in Denmark, a quantitative assessment.

INTRODUCTION: The number of persons with gender incongruence referred to health care is increasing, but national data on the incidence of gender incongruence are lacking. The aim of this study was to quantify the development in number of individuals with gender incongruence over time and to estimate the national incidence in Denmark. MATERIAL AND METHODS: Historical descriptive cohort study. Individuals older than 18 years with legal sex-change in their person registration number were achieved from Statistics Denmark, and the National Health Register provided data on contact diagnoses related to gender-identity conditions. By combining these two data sources, we made estimates on incidence and incidence rates for individuals with gender incongruence in Denmark through a 41-year period 1980-2020. RESULTS: Through 1980-2020, the annual number of legal sex-changes increased in individuals assigned female at birth from 5 to approximately 170 and among individuals assigned male at birth from 10 to approximately 150. The cumulative number of legal sex-changes at the end of 2019 was 1275 assigned female at birth and 1422 assigned male at birth and 66% of the legal sex-changes were in individuals below 30 years. Correspondingly, the annual number of contacts with the healthcare system due for gender-identity-related conditions increased from 30 during 1990-1999 to around 500 in 2017 (both genders combined), with a 10-fold increase from 2010 to 2017. CONCLUSIONS: The number of legal sex-changes and healthcare contacts due to gender-identity-related diagnoses increased substantially over the last 40 years with a more than 10-fold increase during the last decade. This calls for research on possible explanations for this increase, for research on the short-term and long-term health consequences of hormonal and surgical treatment regimens and for ensuring adequate healthcare facilities.

Pregnancy loss is associated with type 2 diabetes: a nationwide case-control study.

AIMS/HYPOTHESIS: Type 2 diabetes is killing more people than ever, and early-life predictors remain critical for the development of effective preventive strategies. Pregnancy loss is a common event associated with later atherosclerotic disease and ischaemic heart failure and might constitute a predictor for type 2 diabetes. The objective of this study was to investigate whether pregnancy loss is associated with later development of type 2 diabetes. METHODS: Using a Danish nationwide cohort, we identified all women born from 1957 through to 1997 and who had a diagnosis of type 2 diabetes during the period 1977 to 2017. The women were matched 1:10 on year of birth and educational level to women without diabetes in the general Danish population. Conditional logistic regression models provided odds ratios for type 2 diabetes with different numbers of pregnancy losses. RESULTS: We identified 24,774 women with type 2 diabetes and selected 247,740 controls without diabetes. Women who had ever been pregnant (ever-pregnant women) with 1, 2 and ≥ 3 pregnancy losses had ORs of type 2 diabetes of 1.18 (95% CI 1.13, 1.23), 1.38 (95% CI 1.27, 1.49) and 1.71 (95% CI 1.53, 1.92) compared with ever-pregnant women with no pregnancy losses, respectively. Women who never achieved a pregnancy had an OR of type 2 diabetes of 1.56 (95% CI 1.51, 1.61) compared with ever-pregnant women with any number of losses. Similar results were found after adjustment for obesity and gestational diabetes. CONCLUSIONS/INTERPRETATION: We found a significant and consistent association between pregnancy loss and later type 2 diabetes that increased with increasing number of losses. Thus, pregnancy loss and recurrent pregnancy loss are significant risk factors for later type 2 diabetes. Future studies should explore whether this association is due to common background factors or whether prediabetic metabolic conditions are responsible for this association. Graphical abstract.

Pregnancy loss: A 40-year nationwide assessment.

INTRODUCTION: Pregnancy loss is frequent. We aimed to assess the frequency and trends in pregnancy losses according to female age and mode of conception over a 40-year follow-up period. MATERIAL AND METHODS: In a national historical prospective cohort study, we followed all Danish women 10-49 years over the 40-year study period 1978-2017. Data on pregnancies and their outcomes were obtained from the National Health Registry, the Medical Birth Registry and the National Fertility Registry. Incidence rates per 100 pregnancies and per 1,000 women-years as well as lifetime risks per 100 women were calculated. Women included in the lifetime analysis were followed from age 12 to age 49. Pregnancy loss included spontaneous abortion, missed abortion and anembryonic pregnancy. RESULTS: In 3 519 455 recorded pregnancies, 337 008, or 9.6%, were diagnosed with a pregnancy loss. The proportion increased from 7.5% in 1978-1979, peaked at 10.7% in 2000 and thereafter decreased to 9.1% in 2015-2017. Pregnancy loss rate in women 10-14 years was 3.9%, increasing gradually with age to 26.9% in pregnant women 45-49 years, a 6.9-fold increase. Loss rates were slightly lower in naturally conceived pregnancies than in assisted pregnancies except for women above 45 years, where the risk of loss was higher in the spontaneously conceived group. Lifetime risk of specific numbers of losses were: 0: 76.9%, 1: 17.9%, 2: 3.9%, 3: 0.87%, and 4+: 0.35%. CONCLUSIONS: The proportion of women experiencing pregnancy loss has changed little throughout four decades and is still primarily influenced by female age. More than 75% of pregnant women are never recorded with a pregnancy loss, and <1.5% will experience three or more losses.

Maternal age and risk of cesarean section in women with induced labor at term-A Nordic register-based study.

INTRODUCTION: Over the last decades, induction of labor has increased in many countries along with increasing maternal age. We assessed the effects of maternal age and labor induction on cesarean section at term among nulliparous and multiparous women without previous cesarean section. MATERIAL AND METHODS: We performed a retrospective national registry-based study from Denmark, Finland, Iceland, Norway, and Sweden including 3 398 586 deliveries between 2000 and 2011. We investigated the impact of age on cesarean section among 196 220 nulliparous and 188 158 multiparous women whose labor was induced, had single cephalic presentation at term, and no previous cesarean section. Confounders comprised country, time-period, and gestational age. RESULTS: In nulliparous women with induced labor the rate of cesarean section increased from 14.0% in women less than 20 years of age to 39.9% in women 40 years and older. Compared with women aged 25-29 years, the corresponding relative risks were 0.60 (95% confidence interval [95% CI] 0.57 to 0.64) and 1.72 (95% CI 1.66 to 1.79). In multiparous induced women the risk of cesarean section was 3.9% in women less than 20 years rising to 9.1% in women 40 years and older. Compared with women aged 25-29 years, the relative risks were 0.86 (95% CI 0.54 to 1.37) and 1.98 (95% CI 1.84 to 2.12), respectively. There were minimal confounding effects of country, time-period, and gestational age on risk for cesarean section. CONCLUSIONS: Advanced maternal age is associated with increased risk of cesarean section in women undergoing labor induction with a single cephalic presentation at term without a previous cesarean section. The absolute risk of cesarean section is 3-5 times higher across 5-year age groups in nulliparous relative to multiparous women having induced labor.

Reduced Complications Following Implementation of Laparoscopic Hysterectomy: A Danish Population-based Cohort Study of Minimally Invasive Benign Gynecologic Surgery between 2004 and 2018.

STUDY OBJECTIVE: To monitor and report nationwide changes in the rates of and complications after different methods for benign hysterectomy, operative hysteroscopy, myomectomy, and embolization in Denmark. To report the national mortality after benign hysterectomy DESIGN: National prospective, observational cohort study. SETTING: The Danish Hysterectomy and Hysteroscopy Database. PATIENTS: Women undergoing surgery for benign gynecologic diseases: 64 818 hysterectomies, 84 175 hysteroscopies, 4016 myomectomies, and 1209 embolizations in Denmark between 2004 and 2018. INTERVENTIONS: National meetings with representatives from all departments, annual working reports of institutional complication rates, workshops, and national guideline initiative to improve minimally invasive surgical methods. MEASUREMENTS AND MAIN RESULTS: Rates of the different methods and complications after each method with follow-up to 5 years as recorded by the database directly in the National Patient Registry. Nationwide, a decline in the use of hysterectomy, myomectomy, embolizations, and endometrial ablation. The total short-term complications were 9.8%, 7.5%, 8.9%, and 2.7% respectively, however, with a persistent risk of approximately 20% for recurrent operations within 5 years after endometrial ablation. Initially, we urged for increased use of vaginal hysterectomy, but only reached 36%. From 2010, we urged for reducing abdominal hysterectomies by implementing laparoscopic hysterectomy and reached 72% laparoscopic and robotic procedures. Since 2015, we used coring or contained morcellation for removal of large uterus at laparoscopic hysterectomy. The major and minor complication rates (modified Clavien-Dindo classification) were reduced significantly from 8.1% to 4.1% and 9.9% to 5.7% respectively. Mortality after benign hysterectomy was 0.27‰. The odds ratio for major complications after abdominal hysterectomy was 1.66 (1.52-1.81) compared to minimally invasive hysterectomy independent of the length of stay, high-volume departments, indications, comorbidity, age, and calendar year. CONCLUSION: Fifteen years with a national database has resulted in a marked quality improvement. Denmark has 85% minimally invasive hysterectomies and has reduced the number of major complications by 50%.

Relation Between Infant Microbiota and Autism?: Results from a National Cohort Sibling Design Study.

BACKGROUND: Hypotheses concerning adverse effects of changes in microbiota have received much recent attention, but unobserved confounding makes them difficult to test. We investigated whether surrogate markers for potential adverse microbiota change in infancy affected autism risk, addressing unobserved confounding using a sibling study design. METHODS: This is a population-based, prospective cohort study including all singleton live births in Denmark from 1997 to 2010. The exposure variables were cesarean delivery and antibiotic use in the first 2 years of life. The outcome was a subsequent autism diagnosis. We used the between- and within-sibling model and compared it with sibling-stratified Cox models and simpler standard Cox models that ignored sibship. RESULTS: Of our study population including 671,606 children, who were followed for up to 15 years (7,341,133 person-years), 72% received antibiotics, 17.5% were delivered by cesarean, and 1.2% (8,267) developed autism. The standard Cox models predicted that both cesarean (compared with vaginal) delivery and antibiotics increased the risk of autism. In the sibling-stratified Cox model, only broader spectrum antibiotics were associated with increased risk of autism: hazard ratio (HR) = 1.16 (95% confidence interval = 1.01, 1.36). The between-within model estimated no exposure effects: intrapartum cesarean HR = 1.06 (0.89, 1.26); prelabor cesarean HR = 0.97 (0.83, 1.15); exclusively penicillin HR = 1.05 (0.93, 1.18); and broader spectrum antibiotics HR = 1.05 (0.95, 1.16). CONCLUSIONS: The between-within model rendered more precise estimates than sibling-stratified Cox models, and we believe that it also provided more valid estimates. Results from these preferred models do not support a causal relation between antibiotic treatment during infancy, cesarean delivery, and autism. See video abstract at, http://links.lww.com/EDE/B432.

Investigating the effects of cesarean delivery and antibiotic use in early childhood on risk of later attention deficit hyperactivity disorder.

BACKGROUND: Increasing attention deficit hyperactivity disorder (ADHD) incidence has been proposed to be caused by factors influencing microbiota in early life. We investigated the potential causality between ADHD and two surrogate markers for changes in children's microbiota: birth delivery mode and early childhood antibiotic use. METHOD: This population-based, prospective cohort study linked nationwide registers of data for native Danish singleton live births in Denmark from 1997 to 2010. Exposure variables were delivery mode and antibiotic use during the first 2 years of life. The main outcome measure was ADHD diagnosis or redeemed ADHD medication prescriptions. For statistical analysis, we used both advanced sibling models and a more traditional approach. RESULTS: We included 671,592 children, followed from their second birthday in the period 1999-2014 for 7,300,522 person-years. ADHD was diagnosed in 17,971. In total, 17.5% were born by cesarean delivery, and 72% received antibiotic treatment within their first 2 years of life. In the adjusted between-within sibling survival model, mode of delivery or antibiotics had no effect on ADHD when compared with vaginal delivery or no antibiotic treatment as hazard ratios were 1.09 (95% confidence interval 0.97-1.24) for intrapartum cesarean, 1.03 (0.91-1.16) for prelabor cesarean, 0.98 (0.90-1.07) for penicillin, and 0.99 (0.92-1.06) for broader spectrum antibiotics. In a sibling-stratified Cox regression, intrapartum cesarean was associated with increased ADHD risk, but other exposures were not. In a descriptive, nonstratified Cox model, we found increased risk for ADHD for all exposures. CONCLUSIONS: Detailed family confounder control using the superior between-within model indicates that cesarean delivery or use of antibiotics during the first 2 years of life does not increase ADHD risk. Therefore, our study suggests that changes in children's microbiota related to cesarean delivery or antibiotic use, do not cause ADHD.

Two Modes of Evolution: Optimization and Expansion.

We document and discuss two different modes of evolution across multiple systems, optimization and expansion. The former suffices in systems whose size and interactions do not change substantially over time, while the latter is a key property of open-ended evolution, where new players and interaction types enter the game. We first investigate systems from physics, biology, and engineering and argue that their evolutionary optimization dynamics is the cumulative effect of multiple independent events, or quakes, which are uniformly distributed on a logarithmic time scale and produce a decelerating fitness improvement when using the appropriate independent variable. The appropriate independent variable can be physical time for a disordered magnetic system, the number of generations for a bacterial system, or the number of produced units for a particular technological product. We then derive and discuss a simple microscopic theory that explains the nature of the involved optimization processes, and provide simulation results as illustration. Finally, we explore the evolution of human culture and technology, using empirical economic data as a proxy for human fitness. Assuming the overall dynamics is a combined optimization and expansion process, the two processes can be separated and quantified by superimposing the mathematical form of an optimization process on the empirical data and thereby transforming the independent variable. This variable turns out to increase faster than any exponential function of time, a property likely due to strong historical changes in the web of human interactions and to the associated increase in the amount of available knowledge. A microscopic theory for this time dependence remains, however, a challenging open problem.

Open-Ended Evolution and Open-Endedness: Editorial Introduction to the Open-Ended Evolution I Special Issue.

Nature's spectacular inventiveness, reflected in the enormous diversity of form and function displayed by the biosphere, is a feature of life that distinguishes living most strongly from nonliving. It is, therefore, not surprising that this aspect of life should become a central focus of artificial life. We have known since Darwin that the diversity is produced dynamically, through the process of evolution; this has led life's creative productivity to be called Open-Ended Evolution (OEE) in the field. This article introduces the first of two special issues on current research on OEE and on the more general concept of open-endedness. Most of the papers presented in these special issues are elaborations of work presented at the Third Workshop on Open-Ended Evolution, held in Tokyo as part of the 2018 Conference on Artificial Life.

An Overview of Open-Ended Evolution: Editorial Introduction to the Open-Ended Evolution II Special Issue.

Nature's spectacular inventiveness, reflected in the enormous diversity of form and function displayed by the biosphere, is a feature of life that distinguishes living most strongly from nonliving. It is, therefore, not surprising that this aspect of life should become a central focus of artificial life. We have known since Darwin that the diversity is produced dynamically, through the process of evolution; this has led life's creative productivity to be called Open-Ended Evolution (OEE) in the field. This article introduces the second of two special issues on current research in OEE and provides an overview of the contents of both special issues. Most of the work was presented at a workshop on open-ended evolution that was held as a part of the 2018 Conference on Artificial Life in Tokyo, and much of it had antecedents in two previous workshops on open-ended evolution at artificial life conferences in Cancun and York. We present a simplified categorization of OEE and summarize progress in the field as represented by the articles in this special issue.

Use of prophylactic Saccharomyces boulardii to prevent Clostridium difficile infection in hospitalized patients: a controlled prospective intervention study.

Clostridium difficile infection (CDI) is a common complication to antibiotic use. Saccharomyces boulardii has shown effect as a prophylactic agent. We aimed to evaluate the efficacy of S. boulardii in preventing CDI in unselected hospitalized patients treated with antibiotics. We conducted a 1 year controlled prospective intervention study aiming to prescribe Sacchaflor (S. boulardii 5 × 109, Pharmaforce ApS) twice daily to hospitalized patients treated with antibiotics. Comparable departments from three other hospitals in our region were included as controls. All occurrences of CDI in patients receiving antibiotics were reported and compared to a baseline period defined as 2 years prior to intervention. Results were analyzed using run chart tests for non-random variation in CDI rates. In addition, odds ratios for CDI were calculated. S. boulardii compliance reached 44% at the intervention hospital, and 1389 patients were treated with Sacchaflor. Monthly CDI rates dropped from a median of 3.6% in the baseline period to 1.5% in the intervention period. S. boulardii treatment was associated with a reduced risk of CDI at the intervention hospital: OR = 0.06 (95% CI 0.02-0.16). At two control hospitals, CDI rates did not change. At one control hospital, the median CDI rate dropped from 3.5 to 2.4%, possibly reflecting the effects of simultaneous multifaceted intervention against CDI at that hospital. The results from this controlled prospective interventional study indicate that S. boulardii is effective for the prevention of CDI in an unselected cohort of mainly elderly patients from departments of internal medicine.

Can oxytocin augmentation modify the risk of epidural analgesia by maternal age in cesarean sections?

INTRODUCTION: Maternal age is an established risk factor for cesarean section; epidural analgesia and oxytocin augmentation may modify this association. We investigated the effects and interactions of oxytocin augmentation, epidural analgesia and maternal age on the risk of cesarean section. MATERIAL AND METHODS: In all, 416 386 nulliparous women with spontaneous onset of labor, ≥37 weeks of gestation and singleton infants with a cephalic presentation during 2000-2011 from Norway and Denmark were included [Ten-group classification system (Robson) group 1]. In this case-control study the main exposure was maternal age; epidural analgesia, oxytocin augmentation, birthweight and time period were explanatory variables. Chi-square test and logistic regression were used to estimate associations and interactions. RESULTS: The cesarean section rate increased consistently with advancing maternal age, both overall and in strata of epidural analgesia and oxytocin augmentation. We observed strong interactions between maternal age, oxytocin augmentation and epidural analgesia for the risk of cesarean section. Women with epidural analgesia generally had a reduced adjusted odds ratio when oxytocin was used compared with when it was not used. In Norway, this applied to all maternal age groups but in Denmark only for women ≥30 years. Among women without epidural, oxytocin augmentation was associated with an increased odds ratio for cesarean section in Denmark, whereas no difference was observed in Norway. CONCLUSIONS: Oxytocin augmentation in nulliparous women with epidural analgesia is associated with a reduced risk of cesarean section in labor with spontaneous onset.