Development of novel ß2-adrenergic receptor agonists for the stimulation of glucose uptake - The importance of chirality and ring size of cyclic amines.

ß2-Adrenergic receptor (ß2AR) agonists have been reported to stimulate glucose uptake (GU) by skeletal muscle cells and are therefore highly interesting as a possible treatment for type 2 diabetes (T2D). The chirality of compounds often has a great impact on the activity of ß2AR agonists, although this has thus far not been investigated for GU. Here we report the GU for a selection of synthesized acyclic and cyclic ß-hydroxy-3-fluorophenethylamines. For the N-butyl and the N-(2-pentyl) compounds, the (R) and (R,R) (3d and 7e) stereoisomers induced the highest GU. When the compounds contained a saturated nitrogen containing 4- to 7-membered heterocycle, the (R,R,R) enantiomer of the azetidine (8a) and the pyrrolidine (9a) had the highest activity. Altogether, these results provide pivotal information for designing novel ß2AR agonist for the treatment of T2D.

Risk of recurrent red-cell transfusion in delivery: A nationwide longitudinal study.

OBJECTIVE: To investigate the risk of recurrent maternal red-cell transfusion in delivery. DESIGN: Nationwide long-standing retrospective cohort study. SETTING: Swedish medical birth register. POPULATION: All registered births from 2000 to 2017 in Sweden. METHODS: We included all women with between one and three consecutive registered births from 22 weeks of gestation onwards and all maternal red-cell transfusions in the peripartum period within the defined period of study. Information on gestational and non-gestational comorbidity was collected and we identified any female siblings. In our analyses we compared the risk of red-cell transfusion in delivery in relation to transfusion history and gestational and non-gestational comorbidity. MAIN OUTCOME MEASURES: Maternal peripartum red-cell transfusion, defined as a recorded transfusion in the period from 1 day before and 7 days after delivery. RESULTS: We included 825 451 women with a total 1 419 909 deliveries, including 786 097 (55.4%) first, 511 398 (36.0%) second and 122 414 (8.6%) third deliveries. Of women with previous obestric transfusion, 8.7% were transfused in a second delivery, compared with 1.7% of women without transfusion or diagnosis of haemorrhage. A previous diagnosis of haemorrhage did not affect the odds ratio of transfusion recurrence. Among women who were transfused in their first two deliveries, 15.5% were transfused in third delivery, corresponding to an 11-fold increase, compared with non-transfused women (adjusted odds ratio aOR 11.5, 95% CI 7.9-16.6). Women with a sister transfused in delivery were at increased risk of transfusion in a second delivery (aOR 1.8, 95% CI 1.6-2.1). CONCLUSIONS: Women with previous red-cell transfusion are at an increased risk of red-cell transfusion in a subsequent delivery, compared with women without a history of red-cell transfusion.

Severe maternal morbidity surveillance, temporal trends and regional variation: A population-based cohort study.

OBJECTIVE: To quantify temporal trends and regional variation in severe maternal morbidity (SMM) in Sweden. DESIGN: Cohort study. POPULATION: Live birth and stillbirth deliveries in Sweden, 1999-2019. METHODS: Types and subtypes of SMM were identified, based on a standard list (modified for Swedish clinical setting after considering the frequency and validity of each indicator) using diagnoses and procedure codes, among all deliveries at ≥22 weeks of gestation (including complications within 42 days of delivery). Contrasts between regions were quantified using rate ratios (RRs) and 95% confidence intervals (95% CIs). Temporal changes in SMM types and subtypes were described. MAIN OUTCOME MEASURES: Types and subtypes of SMM. RESULTS: There were 59 789 SMM cases among 2 212 576 deliveries, corresponding to 270.2 (95% CI 268.1-272.4) per 10 000 deliveries. Composite SMM rates increased from 236.6 per 10 000 deliveries in 1999 to 307.3 per 10 000 deliveries in 2006, before declining to 253.8 per 10 000 deliveries in 2019. Changes in composite SMM corresponded with temporal changes in severe haemorrhage rates, which increased from 94.9 per 10 000 deliveries in 1999 to 169.3 per 10 000 deliveries in 2006, before declining to 111.2 per 10 000 deliveries in 2019. Severe pre-eclampsia, eclampsia and HELLP (haemolysis, elevated liver enzymes and low platelet count) syndrome (103.8 per 10 000 deliveries), severe haemorrhage (133.7 per 10 000 deliveries), sepsis, embolism, disseminated intravascular coagulation, shock and severe mental health disorders were the most common SMM types. Rates of embolism, disseminated intravascular coagulation and shock, acute renal failure, cardiac complications, sepsis and assisted ventilation increased, whereas rates of surgical complications, severe uterine rupture and anaesthesia complications declined. CONCLUSIONS: The observed spatiotemporal variations in composite SMM and SMM types provide substantive insights and highlight regional priorities for improving maternal health.

Pelvic floor dysfunction after intervention, compared with expectant management, in prolonged second stage of labour: A population-based questionnaire and cohort study.

OBJECTIVE: To investigate the effect of vacuum extraction (VE) or caesarean section (CS), compared with expectant management, on pelvic floor dysfunction (PFD) 1-2 years postpartum in primiparous women with a prolonged second stage of labour. DESIGN: A population-based questionnaire and cohort study. SETTING: Stockholm, Sweden. POPULATION: A cohort of 1302 primiparous women with a second stage duration of ≥3 h, delivering from December 2017 to November 2018. METHODS: The 1-year follow-up questionnaire from the Swedish National Perineal Laceration Register was distributed 12-24 months postpartum. Exposure was VE or CS at 3-4 h or 4-5 h, compared with expectant management. MAIN OUTCOME MEASURES: Pelvic floor dysfunction was defined as at least weekly symptoms of urinary incontinence, pelvic organ prolapse or a Wexner score of ≥4. The risk of PFD was calculated using Poisson regression with robust variance estimation, presented as crude and adjusted relative risks (RRs and aRRs) with 95% confidence intervals (95% CIs). The implication of obstetric anal sphincter injury (OASI) on pelvic floor disorders was investigated through mediation analysis. RESULTS: In total, 35.1% of women reported PFD. Compared with expectant management, the risk of PFD was increased after VE at 3-4 h (aRR 1.33, 95% CI 1.06-1.65) and 4-5 h (aRR 1.34, 95% CI 1.05-1.70), but remained unchanged after CS. The increased risk after VE was not mediated by OASI. CONCLUSIONS: Pelvic floor dysfunction was common in primiparous women after a prolonged second stage, and the risk of PFD increased after VE but was unaffected by CS, compared with expectant management. If a spontaneous vaginal delivery eventually occurred, allowing an extended duration of labour did not increase the risk of PFD.

Duration of the active first stage of labour and severe perineal lacerations and maternal postpartum complications: a population-based cohort study.

OBJECTIVE: The impact of first stage labour duration on maternal outcomes is sparsely investigated. We aimed to study the association between a longer active first stage and maternal complications in the early postpartum period. DESIGN: A population-based cohort study. SETTING: Regions of Stockholm and Gotland, Sweden, 2008-2020. POPULATION: A cohort of 159 459 term, singleton, vertex pregnancies, stratified by parity groups. METHODS: The exposure was active first stage duration, categorised in percentiles. Poisson regression analysis was performed to estimate the adjusted relative risk (aRR) and the 95% confidence interval (95% CI). To investigate the effect of second stage duration on the outcome, mediation analysis was performed. MAIN OUTCOME MEASURES: Severe perineal lacerations (third or fourth degree), postpartum infection, urinary retention and haematoma in the birth canal or ruptured sutures. RESULTS: The risks of severe perineal laceration, postpartum infection and urinary retention increased with a longer active first stage, both overall and stratified by parity group. The aRR increased with a longer active first stage, using duration of <50th percentile as the reference. In the ≥90th percentile category, the aRR for postpartum infection was 1.64 (95% CI 1.46-1.84) in primiparous women, 2.43 (95% CI 1.98-2.98) in parous women with no previous caesarean delivery (CD) and 2.33 (95% CI 1.65-3.28) in parous women with a previous CD. The proportion mediated by second stage duration was 33.4% to 36.9% for the different outcomes in primiparous women. The risk of haematoma or ruptured sutures did not increased with a longer active first stage. CONCLUSIONS: Increasing active first stage duration is associated with maternal complications in the early postpartum period.

Latent phase duration and associated outcomes: a contemporary, population-based observational study.

BACKGROUND: Little is known about the latent phase of labor, including whether its duration influences subsequent labor processes or birth outcomes. OBJECTIVE: This study aimed to describe the duration of the latent phase of labor from self-report of the onset of painful contractions to a cervical dilation of 5 cm in a large, Swedish population and evaluate the association between the duration of the latent phase of labor and perinatal processes and outcomes that occurred during the active phase of labor, second stage of labor, birth and immediately after delivery, stratified by parity. STUDY DESIGN: This was a population-based cohort study of 67,267 pregnancies with deliveries between 2008 and 2020 in the Stockholm-Gotland Regions, Sweden. Nulliparous and parous women without a history of cesarean delivery in spontaneous labor with a term (≥37 weeks of gestation), singleton, live, and vertex fetus without major malformations were included. Imputation was used if the notation of the end of the latent phase of labor (ie, cervical dilation of 5 cm) was missing in the partograph. Multivariable logistic regression was used to estimate the association with adjusted odds ratios and 95% confidence intervals, controlling for potential covariates. RESULTS: Including the time from painful contraction onset to a cervical dilation of 5 cm, the median durations of the latent phase of labor were 16.0 (interquartile range, 10.0-26.6) hours for nulliparous women and 9.4 (interquartile range, 5.9-15.3) hours for multiparous women. The durations of the latent phase of labor beyond the median were associated with increased odds of labor dystocia diagnosis during the first stage active phase or second stage of labor and interventions commonly associated with dystocia (amniotomy, oxytocin augmentation, epidural, and cesarean delivery). The duration of the latent phase of labor of ≥90th percentile vs less than the median in nulliparous women demonstrated an increased risk of adverse neonatal outcomes (Apgar score of <7 at 5 minutes and neonatal intensive care unit admission), chorioamnionitis, and fetal occiput posterior. In multiparous women, longer duration of the latent phase of labor was associated with an increased risk of neonatal intensive care unit admission and chorioamnionitis but was not associated with an Apgar score of <7 at 5 minutes. The duration of the latent phase of labor was not associated with additional markers of maternal risk. CONCLUSION: The duration of the latent phase of labor in nulliparous women was longer than that of multiparous women at each point of distribution. A longer duration of the latent phase of labor was associated with more frequent dystocia diagnoses and related interventions during the first stage active phase or second stage of labor, including cesarean delivery, nulliparous fetal occiput posterior position, chorioamnionitis, and markers of neonatal morbidity. More research is needed to identify potential mediating paths between the duration of the latent phase of labor and neonatal morbidity.

The Stockholm-Gotland perinatal cohort-A population-based cohort including longitudinal data throughout pregnancy and the postpartum period.

BACKGROUND: Register-based reproductive and perinatal databases rarely contain detailed information from medical records or repeated measurements throughout pregnancy and delivery. This lack of enriched pregnancy and birth data led to the initiation of the Swedish Stockholm-Gotland Perinatal Cohort (SGPC). OBJECTIVES: To describe the strengths of the SGPC, as well as the unique research questions that can be addressed using this cohort. POPULATION: The SGPC is a prospectively collected, population-based cohort that includes all births (from 22 completed gestational weeks onwards) between 1 January 2008 and 15 June 2020 in the Stockholm and Gotland regions of Sweden (335,153 singleton and 11,025 multiple pregnancies). DESIGN: Descriptive study. METHODS: The SGPC is based on the electronic medical records of women and their infants. The medical record system is used for all antenatal clinic visits and admissions, delivery and neonatal admissions, as well as postpartum clinical visits. SGPC has been further enriched with data linkages to 10 Swedish National Health Care and Quality Registers. PRELIMINARY RESULTS: In contrast to other reproductive and perinatal databases available in Sweden, including the Medical Birth Register and the Pregnancy Register, SGPC contains highly detailed medical record data, including time-varying serial measurements for physiological parameters throughout pregnancy, delivery, and postpartum, for both mother and infant. These strengths have enabled studies that were previously inconceivable; the effects of serial measurements of pregnancy weight gain, changes in haemoglobin counts and blood pressure during pregnancy, fetal weight estimations by ultrasound, duration of stages and phases of labour, cervical dilatation and oxytocin use during delivery, and constructing reference curves for umbilical cord pH. CONCLUSIONS: The SGPC-with its rich content, repeated measurements and linkages to numerous health care and quality registers-is a unique cohort that enables high-quality perinatal studies that would otherwise not be possible.

The Swedish medical birth register during five decades: documentation of the content and quality of the register.

Pregnancy-related factors are important for short- and long-term health in mothers and offspring. The nationwide population-based Swedish Medical Birth Register (MBR) was established in 1973. The present study describes the content and quality of the MBR, using original MBR data, Swedish-language and international publications based on the MBR.The MBR includes around 98% of all births in Sweden. From 1982 onwards, the MBR is based on prospectively recorded information in standardized antenatal, obstetric, and neonatal records. When the mother and infant are discharged from hospital, this information is forwarded to the MBR, which is updated annually. Maternal data include information from first antenatal visit on self-reported obstetric history, infertility, diseases, medication use, cohabitation status, smoking and snuff use, self-reported height and measured weight, allowing calculation of body mass index. Birth and neonatal data include date and time of birth, mode of delivery, singleton or multiple birth, gestational age, stillbirth, birth weight, birth length, head circumference, infant sex, Apgar scores, and maternal and infant diagnoses/procedures, including neonatal care. The overall quality of the MBR is very high, owing to the semi-automated data extraction from the standardized regional electronic health records, Sweden's universal access to antenatal care, and the possibility to compare mothers and offspring to the Total Population Register in order to identify missing records. Through the unique personal identity numbers of mothers and live-born offspring, the MBR can be linked to other health registers. The Swedish MBR contains high-quality pregnancy-related information on more than 5 million births during five decades.

Comparing the results from a Swedish pregnancy cohort using data from three automated placental growth factor immunoassay platforms intended for first-trimester preeclampsia prediction.

INTRODUCTION: Risk evaluation for preeclampsia in early pregnancy allows identification of women at high risk. Prediction models for preeclampsia often include circulating concentrations of placental growth factor (PlGF); however, the models are usually limited to a specific PlGF method of analysis. The aim of this study was to compare three different PlGF methods of analysis in a Swedish cohort to assess their convergent validity and appropriateness for use in preeclampsia risk prediction models in the first trimester of pregnancy. MATERIAL AND METHODS: First-trimester blood samples were collected in gestational week 11+0 to 13+6 from 150 pregnant women at Uppsala University Hospital during November 2018 until November 2020. These samples were analyzed using the different PlGF methods from Perkin Elmer, Roche Diagnostics, and Thermo Fisher Scientific. RESULTS: There were strong correlations between the PlGF results obtained with the three methods, but the slopes of the correlations clearly differed from 1.0: PlGFPerkinElmer = 0.553 (95% confidence interval [CI] 0.518-0.588) * PlGFRoche -1.112 (95% CI -2.773 to 0.550); r = 0.966, mean difference -24.6 (95% CI -26.4 to -22.8). PlGFPerkinElmer = 0.673 (95% CI 0.618-0.729) * PlGFThermoFisher -0.199 (95% CI -2.292 to 1.894); r = 0.945, mean difference -13.8 (95% CI -15.1 to -12.6). PlGFRoche = 1.809 (95% CI 1.694-1.923) * PlGFPerkinElmer +2.010 (95% CI -0.877 to 4.897); r = 0.966, mean difference 24.6 (95% CI 22.8-26.4). PlGFRoche = 1.237 (95% CI 1.113-1.361) * PlGFThermoFisher +0.840 (95% CI -3.684 to 5.363); r = 0.937, mean difference 10.8 (95% CI 9.4-12.1). PlGFThermoFisher = 1.485 (95% CI 1.363-1.607) * PlGFPerkinElmer +0.296 (95% CI -2.784 to 3.375); r = 0.945, mean difference 13.8 (95% CI 12.6-15.1). PlGFThermoFisher = 0.808 (95% CI 0.726-0.891) * PlGFRoche -0.679 (95% CI -4.456 to 3.099); r = 0.937, mean difference -10.8 (95% CI -12.1 to -9.4). CONCLUSION: The three PlGF methods have different calibrations. This is most likely due to the lack of an internationally accepted reference material for PlGF. Despite different calibrations, the Deming regression analysis indicated good agreement between the three methods, which suggests that results from one method may be converted to the others and hence used in first-trimester prediction models for preeclampsia.

Association Between History of Adverse Pregnancy Outcomes and Coronary Artery Disease Assessed by Coronary Computed Tomography Angiography.

Importance: Adverse pregnancy outcomes are recognized risk enhancers for cardiovascular disease, but the prevalence of subclinical coronary atherosclerosis after these conditions is unknown. Objective: To assess associations between history of adverse pregnancy outcomes and coronary artery disease assessed by coronary computed tomography angiography screening. Design, Setting, and Participants: Cross-sectional study of a population-based cohort of women in Sweden (n = 10 528) with 1 or more deliveries in 1973 or later, ascertained via the Swedish National Medical Birth Register, who subsequently participated in the Swedish Cardiopulmonary Bioimage Study at age 50 to 65 (median, 57.3) years in 2013-2018. Delivery data were prospectively collected. Exposures: Adverse pregnancy outcomes, including preeclampsia, gestational hypertension, preterm delivery, small-for-gestational-age infant, and gestational diabetes. The reference category included women with no history of these exposures. Main Outcomes and Measures: Coronary computed tomography angiography indexes, including any coronary atherosclerosis, significant stenosis, noncalcified plaque, segment involvement score of 4 or greater, and coronary artery calcium score greater than 100. Results: A median 29.6 (IQR, 25.0-34.9) years after first registered delivery, 18.9% of women had a history of adverse pregnancy outcomes, with specific pregnancy histories ranging from 1.4% (gestational diabetes) to 9.5% (preterm delivery). The prevalence of any coronary atherosclerosis in women with a history of any adverse pregnancy outcome was 32.1% (95% CI, 30.0%-34.2%), which was significantly higher (prevalence difference, 3.8% [95% CI, 1.6%-6.1%]; prevalence ratio, 1.14 [95% CI, 1.06-1.22]) compared with reference women. History of gestational hypertension and preeclampsia were both significantly associated with higher and similar prevalence of all outcome indexes. For preeclampsia, the highest prevalence difference was observed for any coronary atherosclerosis (prevalence difference, 8.0% [95% CI, 3.7%-12.3%]; prevalence ratio, 1.28 [95% CI, 1.14-1.45]), and the highest prevalence ratio was observed for significant stenosis (prevalence difference, 3.1% [95% CI, 1.1%-5.1%]; prevalence ratio, 2.46 [95% CI, 1.65-3.67]). In adjusted models, odds ratios for preeclampsia ranged from 1.31 (95% CI, 1.07-1.61) for any coronary atherosclerosis to 2.21 (95% CI, 1.42-3.44) for significant stenosis. Similar associations were observed for history of preeclampsia or gestational hypertension among women with low predicted cardiovascular risk. Conclusions and Relevance: Among Swedish women undergoing coronary computed tomography angiography screening, there was a statistically significant association between history of adverse pregnancy outcomes and image-identified coronary artery disease, including among women estimated to be at low cardiovascular disease risk. Further research is needed to understand the clinical importance of these associations.

Laparoscopic cholecystectomy prevents readmissions. A 9-year review of acute pancreatitis in pregnancy in an Australian tertiary center.

BACKGROUND: Acute pancreatitis in pregnancy (APIP) is a rare but potentially life-threatening condition, affecting women at any gestation. The aim of this review is to investigate the demographics, etiology, management, and outcomes of pancreatitis in pregnant women in a major tertiary hospital in Queensland. METHODS: Data was collected from the hospital medical records of all patients diagnosed with APIP from 01/01/2012 until 30/04/2021 at the Mater Hospital, Brisbane. Descriptive statistical measures were employed. Spearman's rank correlation was used to challenge different risk factors for readmission. RESULTS: 26 patients met the inclusion criteria, with 38 admissions during the study period. Biliary pancreatitis was the most common etiology (n = 14, 53.8%). 42.5% of admissions were managed operatively (n = 15). 38.5% of patients had more than one admission (n = 10). Undergoing a laparoscopic cholecystectomy on index admission correlated with a significantly lower chance of repeat admission (rs= -.48, p = .013, CI = - .737 to -.102). CONCLUSION: This is the first study of this condition in an Australian institution. It demonstrates that in patients with acute biliary pancreatitis, operative management can be safely employed at any trimester and laparoscopic cholecystectomies should be performed in the index admission to reduce the risk of readmission to hospital.

Identification of risk factors for incident cervical insufficiency in nulliparous and parous women: a population-based case-control study.

BACKGROUND: Cervical insufficiency is one of the underlying causes of late miscarriage and preterm birth. Although many risk factors have been identified, the relative magnitude of their association with risk in nulliparous versus parous women has not been well demonstrated, especially for incident cervical insufficiency (ICI). The aim of this study was to investigate and compare the magnitude of the association of ICI with predictive factors in nulliparous and parous women, and to further investigate various aspects of obstetric history for parous women. METHODS: Pregnant women with a first diagnosis of cervical insufficiency were compared to a random sample of control pregnancies from women with no diagnosis by using Swedish national health registers. Demographic, reproductive, and pregnancy-specific factors were compared in case and control pregnancies, and relative risks presented as odds ratios (OR), stratified by nulliparous/parous. Independent associations with ICI were estimated from multivariable logistic regression. Associations with obstetric history were further estimated for multiparous women. RESULTS: A total of 759 nulliparous ICI cases and 1498 parous cases were identified during the study period. Multifetal gestation had a strong positive association with ICI in both groups, but of much larger magnitude for nulliparous women. The number of previous miscarriages was also a much stronger predictor of risk in nulliparous women, especially for multifetal pregnancies. History of preterm delivery (<37 weeks' gestation) was an independent predictor for parous women, and for those whose most recent delivery was preterm, the association with ICI increased with each additional week of prematurity. A previous delivery with prolonged second stage of labor or delivery of a very large infant were both inversely associated with risk of ICI in the current pregnancy. CONCLUSIONS: The differences in importance of predictive risk factors for incident cervical insufficiency in nulliparous and parous women can help resolve some of the inconsistencies in the literature to date regarding factors that are useful for risk prediction. Stratifying on parity can inform more targeted surveillance of at-risk pregnancies, enable the two groups of women to be better informed of their risks, and eventually inform screening and intervention efforts.

Association between first and second stage of labour duration and mode of delivery: A population-based cohort study.

BACKGROUND: Active first stage of labour duration can widely vary between women. However, the nature of the relationship between the active first stage and second stage of labour duration is sparsely studied. OBJECTIVES: To determine whether active first stage of labour duration (i) influences second stage of labour duration; and (ii) is associated with mode of delivery. METHODS: A population-based cohort study of 13,379 women primiparous women, with spontaneous start in Stockholm-Gotland Region, Sweden, between 2008 and 2014. Duration of the active first stage of labour was examined in relation to second-stage duration using univariate and multivariable quantile regressions, with the first quartile (first stage duration) as the reference. Nonlinearity of associations was tested by restricted cubic splines. Association between active first-stage duration with mode of delivery was estimated using a multinomial logistic regression based on adjusted odds ratios. RESULTS: Longer active first stage of labour duration was linearly associated with longer second stage of labour duration until approximately 12 h of active first stage of labour duration. After 12 h, a non-linear trend is seen, demonstrated by a plateau in the second-stage duration. In addition, longer active first stage of labour duration was associated with increased occurrence of operative vaginal delivery (adjusted odds ratio 3.36, 95% confidence interval [CI] 2.89, 3.89) and caesarean delivery (adjusted odds ratio 4.75, 95% CI 3.85, 5.80). CONCLUSIONS: Among primiparous women with spontaneous onset of labour, longer active first stage of labour duration was associated with both longer second stage of labour duration and higher odds of operative delivery. This study contributes with findings, which may inform future discussions regarding how to properly account for second-stage duration, with applications in obstetric and perinatal epidemiology.

Aspirin use during pregnancy and the risk of bleeding complications: a Swedish population-based cohort study.

BACKGROUND: Aspirin is offered to pregnant women to prevent preeclampsia, a severe obstetrical complication. Large studies of nonpregnant populations have consistently shown that aspirin prophylaxis increases the risk of hemorrhagic complications. However, there have not been any population-based studies investigating this in a pregnant population. OBJECTIVE: This study aimed to investigate whether aspirin use during pregnancy is associated with an increased risk of bleeding complications. STUDY DESIGN: We performed a register-based cohort study using the Swedish Pregnancy Register wherein we examined 313,624 women giving birth between January 2013 and July 2017. Logistic regression was used to assess the risk of antepartum, intrapartum, and postpartum hemorrhage. A propensity score and inverse probability treatment weighting was used to generate an odds ratio that corrects for differences in baseline characteristics. RESULTS: Aspirin use was registered in 4088 (1.3%) women during pregnancy. Compared with women who did not take aspirin, aspirin use was not associated with bleeding complications during the antepartum period (adjusted odds ratio, 1.22; 95% confidence interval, 0.97-1.54). However, aspirin users had a higher incidence of intrapartum bleeding (2.9% aspirin users vs 1.5% nonusers; adjusted odds ratio, 1.63; 95% confidence interval, 1.30-2.05), postpartum hemorrhage (10.2% vs 7.8%; adjusted odds ratio, 1.23; 95% confidence interval, 1.08-1.39), and postpartum hematoma (0.4% vs 0.1%; adjusted odds ratio, 2.21; 95% confidence interval, 1.13-4.34). The risk of a neonatal intracranial hemorrhage was also increased (0.07% vs 0.01%; adjusted odds ratio, 9.66; 95% confidence interval, 1.88-49.48). After stratifying by mode of birth, a higher incidence of bleeding among aspirin users was present for those who had a vaginal birth but not those who had a cesarean delivery. CONCLUSION: Using aspirin during pregnancy is associated with increased postpartum bleeding and postpartum hematoma. It may also be associated with neonatal intracranial hemorrhage. When offering aspirin during pregnancy, these risks need to be weighed against the potential benefits.

Patterns of red-cell transfusion use in obstetric practice in sweden 2003-2017: A nationwide study.

BACKGROUND: There is a paucity of data on patterns of red-cell transfusions in obstetrical care, but some studies have suggested an increase in transfusion rates during the last decade. The purpose of this study was to investigate maternal characteristics, temporal trends and hospital variations in red-cell use in a large contemporary obstetric cohort in Sweden. STUDY DESIGN AND METHODS: Nationwide observational cohort study of maternal red-cell transfusions for all deliveries in Sweden between 2003 and 2017. RESULTS: The proportion of deliveries that received red-cell transfusions was stable during the study period, although the number of red-cell units administered per delivery declined. Among transfused women, most received a low-volume transfusion of 1 or 2 units. Red-cell transfusion was more common among the nulliparous, for instrumental and caesarean deliveries, and with increased maternal age. We saw large variations in transfusion rates between hospitals in Sweden, despite adjusting for age and parity. CONCLUSIONS: In comparison to other high-resource countries we see a high proportion of deliveries with maternal red-cell transfusions. However, we do not see an increase in red-cell use over time.

Treatment with a ß-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity.

AIMS/HYPOTHESIS: Chronic stimulation of ß2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of ß2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of ß2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. METHODS: C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. RESULTS: Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg-1 day-1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%, p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 ± 0.31%/min in comparison with 0.15 ± 0.36%/min in control mice, p < 0.05) and drastically reduced hepatic steatosis (by 40%, p < 0.01) and glycogen (by 23%, p < 0.05). CONCLUSIONS/INTERPRETATION: Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective ß2-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans. Graphical abstract.

Placental location and risk of retained placenta in women with a previous cesarean section: A population-based cohort study.

INTRODUCTION: Some studies have shown that women with a previous cesarean section, compared with women with a previous vaginal delivery, have an increased risk of retained placenta during a subsequent vaginal delivery. It is unknown whether this is mediated by anterior placental location, when the placenta might cover the uterine scar. The aim of this study was to evaluate whether the increased risk of retained placenta in women with a previous cesarean section is mediated by anterior placental location. MATERIAL AND METHODS: This is a population-based cohort study, with data from the regional population-based Stockholm-Gotland Obstetric Cohort, Sweden, from 2008 to 2014. The overall study population included 49 598 women with a vaginal second delivery, where adequate information about placental location from the second-trimester ultrasound scan was available. For the main analysis, including the 3921 women with a previous cesarean section, we calculated the relative risk of retained placenta in women with an anterior placental location, using women with non-anterior placental locations as reference. Relative risks were calculated as odds ratios (OR) with 95% CI. In a second model, adjustments were made for maternal age, height, country of birth, smoking in early pregnancy, infant sex, and in vitro fertilization. RESULTS: In the overall study population, the rate of retained placenta at the second delivery was 2.0%. The proportion of women with a retained placenta was higher among women with a previous cesarean compared with those with a previous vaginal delivery (3.4% vs 1.9%; P < .0001). In the main analysis, including women with a previous cesarean section, the risk for retained placenta was not increased with anterior compared with non-anterior placental location (OR 0.84, 95% CI 0.60-1.20). Adjustments did not affect the estimates in a significant way. CONCLUSIONS: The increased risk of retained placenta in women with a previous cesarean section is not mediated by anterior placental location.

BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via ß2-adrenoceptors without causing classical receptor desensitization.

The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual ß2-/ß3-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, ß2-adrenoceptor desensitization, ß-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of ß2-adrenoceptors, with a similar potency and efficacy to that of the nonselective ß-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit ß-arrestin1/2 to the ß2-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a ß2-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.

Placental location and pregnancy outcomes in nulliparous women: A population-based cohort study.

INTRODUCTION: The impact of placenta previa on pregnancy, delivery and infant outcomes has been extensively studied. However, less is known about the possible association of placental location other than previa with pregnancy outcomes. The aim of this study was to investigate if placental location other than previa is associated with adverse pregnancy, delivery and infant outcomes. MATERIAL AND METHODS: This is a population-based cohort study, with data from the regional population-based Stockholm-Gotland Obstetric Cohort, Sweden, from 2008 to 2014. The study population included 74 087 nulliparous women with singleton pregnancies resulting in live-born infants, with information about placental location from the second-trimester ultrasound screening. The association between placental location (fundal, lateral, anterior or posterior) and pregnancy outcomes was estimated using logistic regression analysis. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated, and adjustments were made for maternal age, height, country of birth, smoking in early pregnancy, sex of the infant and in vitro fertilization. Main outcome measures were pregnancy, delivery and infant outcomes. RESULTS: Compared with posterior placental location, fundal and lateral placental locations were associated with a number of adverse pregnancy outcomes, the most important being: very preterm birth (<32 weeks of gestation) (adjusted OR [aOR] 1.78, 95% CI 1.18-2.63 and aOR 2.12, 95% CI 1.39-2.25, respectively), moderate preterm birth (32-36 weeks of gestation) (aOR 1.23, 95% CI 1.001-1.51 and aOR 1.62, 95% CI 1.32-2.00, respectively), small-for-gestational-age birth (aOR 1.67, 95% CI 1.34-2.07 and aOR 1.77, 95% CI 1.39-2.25, respectively) and manual removal of the placenta in vaginal births (aOR 3.27, 95% CI 2.68-3.99 and aOR 3.27, 95% CI 2.60-4.10, respectively). Additionally, lateral placental location was associated with preeclampsia (aOR 1.30, 95% CI 1.03-1.65) and severe postpartum hemorrhage (aOR 1.42, 95% CI 1.27-1.82). CONCLUSIONS: Compared with posterior placental location, fundal and lateral placental locations are associated with a number of adverse pregnancy, delivery and infant outcomes.

Duration of second stage of labor and instrumental delivery as risk factors for severe perineal lacerations: population-based study.

BACKGROUND: We sought to investigate the impact of the duration of second stage of labor on risk of severe perineal lacerations (third and fourth degree). METHODS: This population based cohort study was conducted in the Stockholm/Gotland region, Sweden, 2008-2014. Study population included 52 211 primiparous women undergoing vaginal delivery with cephalic presentation at term. Unconditional logistic regression analysis was used to calculate crude and adjusted odds ratios (OR), using 95% confidence intervals (CI). Main exposure was duration of second stage of labor, and main outcome was risks of severe perineal lacerations (third and fourth degree). RESULTS: Risk of severe perineal lacerations increased with duration of second stage of labor. Compared with a second stage of labor of 1 h or less, women with a second stage of more than 2 h had an increased risk (aOR 1.42; 95% CI 1.28-1.58). Compared with non-instrumental vaginal deliveries, the risk was elevated among instrumental vaginal deliveries (aOR 2.24; 95% CI 2.07-2.42). The risk of perineal laceration increased with duration of second stage of labor until less than 3 h in both instrumental and non-instrumental vaginal deliveries, but after 3 h, the ORs did not further increase. After adjustments for potential confounders, macrosomia (birth weight > 4 500 g) and occiput posterior fetal position were risk factors of severe perineal lacerations. CONCLUSIONS: The risk of severe perineal laceration increases with duration until the third hour of second stage of labor. Instrumental delivery is the most significant risk factor for severe lacerations, followed by duration of second stage of labor, fetal size and occiput posterior fetal position.