The association between placenta-associated circulating biomarkers and composite adverse delivery outcome of a likely placental cause in healthy post-date pregnancies.

INTRODUCTION: Post-date pregnancies have an increased risk of adverse delivery outcome. Our aim was to explore the association between placenta-associated circulating biomarkers and composite adverse delivery outcome of a likely placental cause in clinically healthy post-date pregnancies. MATERIAL AND METHODS: Women with healthy singleton post-date pregnancies between 40+2 and 42+2  weeks of gestation were recruited to this prospective, observational study conducted at Oslo University Hospital, Norway (NCT03100084). Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the maternal serum samples closest to delivery. The composite adverse delivery outcome included fetal acidemia, low Apgar score (<4 at 1 min or <7 at 5 min), asphyxia, fetal death, assisted ventilation for more than 6 h, meconium aspiration, hypoxic-ischemic encephalopathy, therapeutic hypothermia, operative delivery due to fetal distress, or pathological placental histology findings. Two study-independent senior consultant obstetricians blinded to biomarker results concluded, based on clinical expert opinion, whether the adverse delivery outcomes were most likely associated with placental dysfunction ("likely placental cause") or not. Means were compared using one-way analysis of variance and Bonferroni corrected pairwise comparisons between groups. Receiver operating characteristic (ROC) curves assessed the predictive ability of PlGF, sFlt-1/PlGF ratio, and PlGF <10th centile after adjustment for gestational age at blood sampling. RESULTS: Of 501 pregnancies reviewed for predefined adverse delivery outcomes and for a likely placental cause, 468 were healthy pregnancies and subsequently assigned to either the "uncomplicated" (no adverse outcome, n = 359), "intermediate" (non-placental cause/undetermined, n = 90), or "complicated" (likely placental cause, n = 19) group. There was a significant difference in mean PlGF and sFlt-1/PlGF ratio between the "complicated", "intermediate", and "uncomplicated" groups (108, 185, and 179 pg/mL, p = 0.001; and 48.3, 23.4, and 24.6, p = 0.002, respectively). There was a higher proportion of PlGF concentration <10th centile in the "complicated" group compared with the "intermediate" and "uncomplicated" groups (42.1% vs. 11.1% and 9.5%, p = 0.001). The largest area under the ROC curve for predicting "complicated" outcome was achieved by PlGF concentration and gestational age at blood sampling (0.76; 95% CI 0.65-0.86). CONCLUSIONS: In clinically healthy post-date pregnancies, an antiangiogenic pre-delivery profile (lower PlGF level and higher sFlt-1/PlGF ratio) was associated with composite adverse delivery outcome of a likely placental cause.

The impact of completing upper secondary education - a multi-state model for work, education and health in young men.

BACKGROUND: Completing upper secondary education is associated with higher work participation and less health-related absence from work. Although these outcomes are closely interrelated, most studies focus on single outcomes, using cross-sectional designs or short follow-up periods. As such, there is limited knowledge of the long-term outcomes, and how paths for completers and non-completers unfold over time. In this paper, we use multi-state models for time-to-event data to assess the long-term effects of completing upper secondary education on employment, tertiary education, sick leave, and disability pension over twelve and a half years for young men. METHODS: Baseline covariates and twelve and a half years of follow-up data on employment, tertiary education, sick leave and disability pension were obtained from national registries for all males born in Norway between 1971 and 1976 (n =184951). The effects of completing upper secondary education (by age 23) were analysed in a multi-state framework, adjusting for both individual and family level confounders. All analyses were done separately for general studies and vocational tracks. RESULTS: Completers do better on a range of outcomes compared to non-completers, for both fields of upper secondary education, but effects of completion change over time. The largest changes are for tertiary education and work, with the probability of work increasing reciprocally to the probability of education. Vocational students are quicker to transfer to the labour market, but tend to have more unemployment, sick leave and disability, and the absolute effects of completion on these outcomes are largest for vocational tracks. However, the relative effects of completion are larger for general studies. CONCLUSION: Completing upper secondary education increases long-term work participation and lowers health-related absence for young men, but effects diminish over time. Studies that have used shorter follow-up periods could be overstating the negative effects of dropout on labour market participation. Multi-state models are well suited to analyse data on work, education and health-related absence, and can be useful in understanding the dynamic aspects of these outcomes.

Post-injury use of opioid analgesics in patients with traumatic injury: A registry-based study.

BACKGROUND: Opioid analgesics are commonly used to treat acute and chronic pain following traumatic injury. Psychiatric comorbidity has been reported to be associated with increased pain and persistent opioid use. Our aims were to determine the extent of post-injury opioid use and assess whether pre-injury antidepressant, benzodiazepine, and z-hypnotic drug use is associated with increased post-injury opioid use. METHODS: Data on trauma patients aged 15 years and older included in the Oslo University Hospital Trauma Registry between 2005 and 2014 was linked to data from the Norwegian Prescription Database. We identified opioid dispensing within the first 90 and 365 days following trauma and determined subsequent persistent use. Multivariable logistic regression was applied to examine associations between pre- and post-injury drug use. RESULTS: 3912 of 11,057 patients (35.4%) had opioids dispensed within 90 days after trauma, and 4644 (42.0%) within 365 days. Among 9800 previously opioid-naïve, the proportions were 33.0% and 39.0%, respectively. One year after the first post-injury opioid dispensing, 9.6% of all opioid users and 4.5% of new users were defined as persistent users. Pre-injury benzodiazepine use and z-hypnotic use was associated with new persistent opioid use (adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 1.47-3.45, and aOR 2.04; 95% CI 1.33-3.13, respectively), whereas pre-injury antidepressant use was not (aOR 1.49; 95% CI 0.97-2.30). CONCLUSIONS: Opioid use after trauma is widespread. Development of persistent use is limited, particularly in previously opioid-naïve patients. Pre-injury benzodiazepine or z-hypnotic use seem to increase odds of new persistent use. SIGNIFICANCE STATEMENT: This large registry-based study adds to the body of knowledge on opioid use beyond in-hospital care in patients having sustained traumatic injury, a field which is scarcely investigated and not yet fully understood. It suggests that both previous drug therapy and the nature of opioid treatment initiation may affect outcome. This will help guide clinicians in selecting the appropriate pain management in this patient group.

Predelivery placenta-associated biomarkers and computerized intrapartum fetal heart rate patterns.

Background: Increasing syncytiotrophoblast stress in term and postdate placentas is reflected by increasing antiangiogenic dysregulation in the maternal circulation, with low "proangiogenic" placental growth factor concentrations and increased "antiangiogenic" soluble fms-like tyrosine kinase-1 concentrations. Imbalances in these placenta-associated proteins are associated with intrapartum fetal compromise and adverse pregnancy and delivery outcome. Cardiotocography is widely used to assess fetal well-being during labor, but it is insufficient on its own for predicting adverse neonatal outcome. Development of improved surveillance tools to detect intrapartum fetal stress are needed to prevent neonatal adverse outcome. Objective: This study aimed to assess whether predelivery circulating maternal angiogenic protein concentrations are associated with intrapartum computerized fetal heart rate patterns, as calculated by the Oxford System for computerized intrapartum monitoring (OxSys) 1.7 prototype. We hypothesized that in pregnancies with low "proangiogenic" placental growth factor levels, increased "antiangiogenic" soluble fms-like tyrosine kinase-1 levels, and increased soluble fms-like tyrosine kinase-1-placental growth factor ratio, the OxSys 1.7 prototype will generate more automated alerts, indicating fetal compromise. Our secondary objective was to investigate the relationship between maternal circulating placenta-associated biomarkers and rates of automated alerts in pregnancies with and without adverse neonatal outcome. Study Design: This was an observational prospective cohort study conducted at a single tertiary center from September 2016 to March 2020. Of 1107 singleton pregnancies (gestational week ≥37+0), 956 had available prelabor and predelivery placental growth factor and soluble fms-like tyrosine kinase-1 concentrations and intrapartum cardiotocography recordings. All neonatal and delivery outcomes were externally reviewed and categorized into 2 groups-the "complicated" group (n=32) and the "uncomplicated" group (n=924)-according to predefined adverse neonatal outcome. Eight different cardiotocography features were calculated by OxSys 1.7: baseline at start of cardiotocography, baseline at end of cardiotocography, short-term variation at start, short-term variation at end, nonreactive initial trace, and throughout the entire cardiotocography, maximum decelerative capacity, total number of prolonged decelerations, and OxSys 1.7 alert. OxSys 1.7 triggered an alert if the initial trace was nonreactive or if decelerative capacity and/or the number of prolonged decelerations exceeded a predefined threshold. Included women and attending clinicians were blinded to both biomarker and OxSys 1.7 results. Results: Mean maternal placental growth factor concentration was lower in the group with OxSys 1.7 alert compared with the group without the alert (151 vs 169 pg/mL; P=.04). There was a weak negative correlation between predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation start (r s=-0.068; 95% confidence interval, -0.131 to -0.004; P=.036), predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation end (r s=-0.068; 95% confidence interval, -0.131 to -0.005; P=.036), and high soluble fms-like tyrosine kinase-1-placental growth factor ratio and low short-term variation end (r s=-0.071; 95% confidence interval, -0.134 to -0.008; P=.027). The rate of decelerative capacity alerts increased more rapidly as placental growth factor decreased in the "complicated" compared with the "uncomplicated" group (0% to 17% vs 4% to 8%). Conclusion: More automated alerts indicative of fetal distress were generated by OxSys 1.7 in pregnancies with low maternal predelivery placental growth factor level, in line with likely increasing placental stress toward the end of the pregnancy. An antiangiogenic predelivery profile (lower placental growth factor) increased the rates of alerts more rapidly in pregnancies with adverse neonatal outcome compared with those without. We suggest that future studies developing and testing prediction tools for intrapartum fetal compromise include predelivery maternal placental growth factor measurements.

Relative validity of fruit and vegetable intake estimated from an FFQ, using carotenoid and flavonoid biomarkers and the method of triads.

The aim of the present study was to validate the intakes of fruit, juice and vegetables from an FFQ. In sub-study I (n 147), intakes from the FFQ were evaluated against 7 d weighed food records (WR) and plasma carotenoid concentrations, whereas in sub-study II (n 85), the intakes were evaluated against plasma carotenoid concentrations and amounts of flavonoids in 24 h urine samples. Relative validity was evaluated by comparing median intakes, estimating correlation coefficients and validity coefficients using the method of triads. In sub-study I, we observed no significant difference in daily median fruit intake between the FFQ and the WR, whereas the intake of vegetables was higher from the FFQ than from the WR. The correlations between intakes from the FFQ and the WR ranged from 0·31 to 0·58. In sub-study II, the intakes of fruit and vegetables correlated significantly with plasma carotenoid concentrations and urinary flavonoids. The validity coefficients for the intakes of fruit and vegetables from the FFQ ranged from 0·61 to 0·88 in sub-study I and from 0·60 to 0·94 in sub-study II. In summary, based on the associations observed between intakes from the FFQ and the biomarkers and the FFQ validity coefficients, the FFQ was found valid and suitable for ranking individuals according to their usual intake of fruit, juice and vegetables.

The association of birthweight with age at natural menopause: a population study of women in Norway.

BACKGROUND: Previous studies suggest that birthweight may influence age at natural menopause, but the evidence remains inconclusive. Thus, we aimed to estimate the association of birthweight with age at natural menopause. METHODS: A retrospective population study of 164 608 women in Norway, aged 48-71 years. Data were obtained by two self-administered questionnaires among participants in BreastScreen Norway during 2006-2014. We used Cox proportional hazard models to estimate hazard ratios and logistic regression models to estimate odds ratios of menopause according to birthweight. Restricted cubic splines were applied to allow for possible non-linear associations, and adjustments were made for year and country of birth. RESULTS: Women with birthweight <2500 g were median 51 years at menopause (interquartile range 49-54 years), whereas women with birthweight 3500-3999 g were median 52 years at menopause (interquartile range 49-54 years). The hazard ratio of menopause decreased with increasing birthweight up until 3500 g. At birthweights >3500 g, we estimated no further decrease (P for non-linearity = 0.007). Birthweight at 2500 g increased the odds ratios of menopause before the age of 45 [1.20; 95% confidence interval (CI): 1.14-1.25] and the age of 40 (1.26; 95% CI: 1.15-1.38) compared with birthweight at 3500 g. At birthweights 4000 g and 4500 g, the odds ratio estimates were very similar to the reference group and the CIs overlapped 1.00. CONCLUSIONS: We found a non-linear dose-relationship of birthweight with age at natural menopause, and low birthweight was associated with early natural menopause. Our findings suggest that growth restriction during fetal life may influence the timing of natural menopause.

Maternal placental growth factor and soluble fms-like tyrosine kinase-1 reference ranges in post-term pregnancies: A prospective observational study.

BACKGROUND: Post-term pregnancies have increased risks for adverse fetal and maternal outcomes. Maternal concentrations of the placenta-associated proteins placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) have been identified as predictors for preeclampsia and fetal growth restriction, both syndromes of placental dysfunction. We have proposed that low maternal circulating PlGF and increased sFlt-1 are general markers for syncytiotrophoblast stress, which increases at and beyond term, even in apparently uncomplicated pregnancies. Our aim was to establish circulating PlGF, sFlt-1, and sFlt-1/PlGF reference ranges in healthy post-term pregnancies (gestational week ≥40+2), comparing with healthy term pregnancies and evaluating associations between time to delivery and biomarker percentiles. METHODS: Of 501 healthy, singleton post-term pregnancies prospectively recruited between September 2016 and December 2017 at our tertiary obstetric department, 426 with an uncomplicated delivery outcome contributed PlGF and sFlt-1 serum concentrations for reference range construction. A retrospective, cross-sectional, term group with an uncomplicated delivery outcome (n = 146) served as comparison. Differences in percentile values between groups and confidence intervals were calculated by quantile regression. RESULTS: In post-term pregnancies the 5th, 50th, and 95th percentiles for PlGF were: 70, 172, and 496 pg/mL; for sFlt-1: 2074, 4268, and 9141 pg/mL; and for sFlt-1/PlGF 5.3, 25.5, and 85.2. Quantile regression analyses comparing the post-term to the term group showed for PlGF a trend towards higher 10th through 30th percentiles, for sFlt-1 significantly higher 10th through 80th percentiles, and for sFlt-1/PlGF ratio significantly higher 30th percentile and significantly lower 95th percentile. PlGF below the 5th percentile and sFlt-1/PlGF ratio above the 95th percentile was associated with shorter time to delivery (p = 0.031 and p = 0.025, respectively). CONCLUSIONS: Our findings support the concept of increasing syncytiotrophoblast stress post-term in clinically healthy pregnancies. Whether post-term dysregulated angiogenic markers reflect a biological placental clock merits further investigation.

Association of IL-8 With Infarct Size and Clinical Outcomes in Patients With STEMI.

BACKGROUND: Little is known about the role of interleukin (IL)-8 in patients with acute ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: The aims of this study were to evaluate, in STEMI patients, the temporal profile of IL-8 and possible associations with left ventricular (LV) function and remodeling, infarct size, microvascular obstruction, myocardial salvage, and future clinical events. METHODS: A total of 258 patients with STEMI were included. Blood samples were drawn before and immediately after percutaneous coronary intervention (PCI), at day 1, and after 4 months. Cardiac magnetic resonance imaging was performed in the acute phase and after 4 months. Clinical events were registered during 12 months' follow-up and all-cause mortality after median 70 months' follow-up. RESULTS: Patients with IL-8 levels greater than the median measured both immediately after PCI and at day 1 had larger final infarct size, lower LV ejection fraction, larger increase in LV end-diastolic volume, and higher frequency of microvascular obstruction. After multivariate adjustment, high IL-8 levels at day 1 were associated with an increased risk of developing a large MI and having reduced LV ejection fraction at 4 months, also after adjustment for peak troponin value. Patients with IL-8 levels in the highest quartile measured at all sampling points were more likely to have a clinical event during the first 12 months after the MI and had lower overall survival during long-term follow-up. CONCLUSIONS: High levels of circulating IL-8 were associated with large infarct size, impaired recovery of LV function, and adverse clinical outcome in patients with STEMI, suggesting IL-8 as a future therapeutic target based on its important role in post-infarction inflammation.

The effect of antibiotic prophylaxis guidelines on surgical-site infections associated with cesarean delivery.

OBJECTIVE: To evaluate the effect of Norwegian antibiotic prophylaxis guidelines on rates of superficial and deep surgical-site infections (SSIs) associated with cesarean delivery (CD). METHODS: A cross-sectional study was conducted that analyzed the physician-diagnosed SSIs by regimen of antibiotic prophylaxis among women who underwent planned or emergency CD at one of 42 hospitals between January 1, 2008, and December 31, 2010. The antibiotic prophylaxis regimen was verified using a hospital survey, whereas guideline compliance was assessed as part of the mandatory Norwegian Surveillance System for Healthcare-Associated Infections. RESULTS: Data for 4498 patients were used. Hospitals that practiced antibiotic prophylaxis for all CDs (n=4) provided antibiotics more often in both emergency and planned CDs than did those that used this approach for emergency CDs only (n=33) or had no written guidelines or used prophylaxis on indication only (n=5) (P<0.001). The provision of antibiotic prophylaxis for all cases of CD was associated with markedly lowered rates of superficial SSIs among planned CDs, whereas no differences in rates of deep SSIs were observed between the guidelines in either planned or emergency CDs. CONCLUSION: Hospitals that provided antibiotic prophylaxis to all women undergoing CD reported high compliance and had reduced rates of superficial SSIs among planned CDs.