Initial Pharmacological Characterization of a Major Hydroxy Metabolite of PF-5190457: Inverse Agonist Activity of PF-6870961 at the Ghrelin Receptor.

Preclinical and clinical studies have identified the ghrelin receptor [growth hormone secretagogue receptor (GHSR)1a] as a potential target for treating alcohol use disorder. A recent phase 1a clinical trial of a GHSR1a antagonist/inverse agonist, PF-5190457, in individuals with heavy alcohol drinking identified a previously undetected major hydroxy metabolite of PF-5190457, namely PF-6870961. Here, we further characterized PF-6870961 by screening for off-target interactions in a high-throughput screen and determined its in vitro pharmacodynamic profile at GHSR1a through binding and concentration-response assays. Moreover, we determined whether the metabolite demonstrated an in vivo effect by assessing effects on food intake in male and female rats. We found that PF-6870961 had no off-target interactions and demonstrated both binding affinity and inverse agonist activity at GHSR1a. In comparison with its parent compound, PF-5190457, the metabolite PF-6870961 had lower binding affinity and potency at inhibiting GHSR1a-induced inositol phosphate accumulation. However, PF-6870961 had increased inhibitory potency at GHSR1a-induced ß-arrestin recruitment relative to its parent compound. Intraperitoneal injection of PF-6870961 suppressed food intake under conditions of both food restriction and with ad libitum access to food in male and female rats, demonstrating in vivo activity. The effects of PF-6870961 on food intake were abolished in male and female rats knockout for GHSR, thus demonstrating that its effects on food intake are in fact mediated by the GHSR receptor. Our findings indicate that the newly discovered major hydroxy metabolite of PF-5190457 may contribute to the overall activity of PF-5190457 by demonstrating inhibitory activity at GHSR1a. SIGNIFICANCE STATEMENT: Antagonists or inverse agonists of the growth hormone secretagogue receptor (GHSR)1a have demonstrated substantial potential as therapeutics for alcohol use disorder. We here expand understanding of the pharmacology of one such GHSR1a inverse agonist, PF-5190457, by studying the safety and pharmacodynamics of its major hydroxy metabolite, PF-6870961. Our data demonstrate biased inverse agonism of PF-6870961 at GHSR1a and provide new structure-activity relationship insight into GHSR1a inverse agonism.

Incidences of obstetric outcomes and sample size calculations: A Danish national registry study based on all deliveries from 2008 to 2015.

INTRODUCTION: In high-income countries the majority of pregnancies have a good outcome, and many adverse obstetric outcomes rarely occur. This makes demonstrating clinically relevant and statistically significant effects of new interventions a challenge. The objective of the study was to report incidences of important obstetric outcomes and to calculate sample sizes for tentative studies. MATERIAL AND METHODS: The study was a registry-based study. Data were retrieved from the Danish Medical Birth Registry and included all deliveries in Denmark from 2008 to 2015. The total population included 465 919 deliveries. The study population comprised intended vaginal deliveries with a single fetus in cephalic presentation at term (n = 381 567). Incidences were reported for 20 outcomes considering the relevance for the patients and the severity of the outcomes. We calculated the sample sizes required in tentative obstetric studies to detect risk reductions of 25 and 50%, for tests at the 5% level, using a power of 80 and 90%. For the randomized controlled trials we calculated the sample size required for comparing two proportions with equal-sized groups. For the cohort study we calculated the sample size also required for two proportions but with unequal sized groups. Outcome measures for sample size calculation were neonatal mortality, Apgar score <7 at 5 minutes and emergency cesarean section. RESULTS: The incidence of neonatal mortality, Apgar score <7 at 5 minutes and emergency cesarean section was 0.05, 0.58 and 10.5%, respectively. Using neonatal mortality as the outcome in a tentative randomized controlled trial with an expected risk reduction of 50% and power of 80%, our calculation showed a sample size of 195 036 deliveries. Using Apgar score <7 at 5 minutes or emergency cesarean section as the outcome, 16 254 and 818 deliveries, respectively, were required. In tentative cohort studies, the required sample sizes were larger due to the unequal proportion of exposed/non-exposed women. CONCLUSIONS: Most adverse obstetric outcomes occur rarely; thus, very large sample sizes are required to achieve adequate statistical power in randomized controlled trials. Multicenter studies, international collaborations or alternative study designs to randomized controlled trials could be considered.

Copenhagen Baby Heart Study: a population study of newborns with prenatal inclusion.

Congenital heart diseases (CHDs) are reported in 0.8% of newborns. Numerous factors influence cardiovascular development and CHD prevalence, and possibly also development of cardiovascular disease later in life. However, known factors explain the probable etiology in only a fraction of patients. Past large-scale population-based studies have made invaluable contributions to the understanding of cardiac disease, but none recruited participants prenatally and focused on the neonatal period. The Copenhagen Baby Heart Study (CBHS) is a population-based study of the prevalence, spectrum, and prognosis of structural and functional cardiac abnormalities. The CBHS will also establish normal values for neonatal cardiac parameters and biomarkers, and study prenatal and early childhood factors potentially affecting later cardiovascular disease risk. The CBHS is an ongoing multicenter, prospective study recruiting from second trimester pregnancy (gestational weeks 18-20) (expected n = 25,000). Information on parents, pregnancy, and delivery are collected. After birth, umbilical cord blood is collected for biochemical analysis, DNA purification, and biobank storage. An echocardiographic examination, electrocardiography, and post-ductal pulse oximetry are performed shortly after birth. Infants diagnosed with significant CHD are referred to a specialist or admitted to hospital, depending on CHD severity. CBHS participants will be followed prospectively as part of specific research projects or regular clinical follow-up for CHD. CBHS design and methodology are described. The CBHS aims to identify new mechanisms underlying cardiovascular disease development and new targets for prevention, early detection, and management of CHD and other cardiac diseases presenting at birth or developing later in life.

Socioeconomic Costs and Health Inequalities from Psoriasis: A Cohort Study.

BACKGROUND: To date, there are no nationwide studies of the social and economic burden of psoriasis to patients in Denmark. Incentives for health care management based on patient-related outcomes and value (IMPROVE) in psoriasis and psoriatic arthritis is a project aimed at assisting movement from activity-based to outcome-based health care management. One of the key objectives in IMPROVE is to describe the disease-associated socioeconomic burden of psoriasis. METHODS: A case-matched study of the impact of psoriasis on patients' income, employment and health care costs in Denmark was performed. The IMPROVE study was a retrospective analysis of patients with a hospital diagnosis of psoriasis identified from the Danish National Patient Registry (NPR). In total, 13,025 psoriasis patients and 25,629 matched controls were identified from the NPR. Data from psoriasis patients and matched controls were compared for social and economic factors including income, employment, health care costs and risk of comorbidities. RESULTS: Psoriasis was associated with increased health care costs (mean annual costs +116% compared to control, p < 0.001), peaking in the year of referral to hospital for psoriasis and sustained thereafter. Both direct and indirect costs were significantly higher for patients with psoriasis than controls (p < 0.001). In the years before and immediately following hospital diagnosis, the rates of employment were lower in psoriasis patients than controls. Comorbidities, including cardiovascular (odds ratio 1.93 [95% CI 1.77-2.09]) and psychiatric conditions (odds ratio 2.61 [95% CI 2.30-2.97]), were more prevalent in patients with psoriasis than controls. CONCLUSION: In Denmark, psoriasis has a significant impact on health care costs, income and employment, and is associated with a range of comorbidities.

The impact of a national cardiotocography education program on neonatal and maternal outcomes: A historical cohort study.

INTRODUCTION: Studies indicate an association between errors in cardiotocography (CTG) management and hypoxic brain injuries among newborns. Continuing professional education is recommended. We aimed to examine whether the implementation of a national interprofessional CTG education program in Denmark was associated with a decrease in risk of fetal hypoxia measured by umbilical cord pH < 7.00, 5-minute Apgar score <7 or neonatal therapeutic hypothermia. As a secondary aim, we assessed whether the educational intervention was associated with an increase in operative deliveries. MATERIAL AND METHODS: We conducted a historical cohort study from 2009 to 2015 including all intended vaginal deliveries with liveborn singletons in cephalic presentation and gestational age ≥37 weeks. Data were retrieved from the Medical Birth Register and the National Patient Register. The study period was divided in three: pre-implementation (2009-2012), implementation (2013) and post-implementation (2014-2015). Using logistic regression we estimated odds ratios (OR) of fetal hypoxia outcomes using the pre-implementation period as reference. Analyses were adjusted for potential maternal, neonatal and delivery-associated confounders. Missing data were accounted for by multiple imputation. RESULTS: In all, 331 282 deliveries were included. Overall risks of pH < 7.00, Apgar score <7 and therapeutic hypothermia were respectively 0.45%, 0.58% and 0.06%. Adjusted OR in the post-implementation period were 1.12 (95% confidence interval [CI] 1.00-1.26), 0.99 (95% CI 0.90-1.10) and 1.34 (95% CI 0.99-1.82) for the three outcomes, respectively. The pH missingness equaled 12.4%. Odds of emergency cesarean section was unaltered, whereas the odds of assisted vaginal delivery decreased by 14% (0.86, 95% CI 0.84-0.89). CONCLUSIONS: Healthcare professionals are considered the weakest link of CTG technology. We did not find that increasing healthcare professionals' CTG interpretation skills affected the risk of fetal hypoxia. Missing data for pH values were substantial and represent a limitation of the study. We cannot with certainty rule out that missingness masked a true effect of the intervention. Our study indicates that assisted vaginal deliveries can be decreased without an increased risk of fetal hypoxia. Dilution of effect in a complex clinical setting, rare outcomes, insufficient intervention and a possible overestimation of the impact of errors in CTG management might explain the lack of effect.

Cardiotocography interpretation skills and the association with size of maternity unit, years of obstetric work experience and healthcare professional background: a national cross-sectional study.

INTRODUCTION: We aimed to examine whether cardiotocography (CTG) knowledge, interpretation skills and decision-making measured by a written assessment were associated with size of maternity unit, years of obstetric work experience and healthcare professional background. MATERIAL AND METHODS: A national cross-sectional study in the setting of a CTG teaching intervention involving all 24 maternity units in Denmark. Participants were midwives (n = 1260) and specialists (n = 269) and residents (n = 142) in obstetrics and gynecology who attended a 1-day CTG course and answered a 30-item multiple-choice question test. Associations between mean test score and work conditions were analyzed using multivariable robust regression, in which the three variables were mutually adjusted. RESULTS: Participants from units with > 3000 deliveries/year scored higher on the test than participants from units with < 1000 deliveries/year (3000-3999 deliveries/year: mean difference 0.8, p < 0.0001; > 4000 deliveries/year: mean difference 0.5, p = 0.006). Participants with < 15 years of work experience scored higher than participants with > 15 years of experience (15-20 years of experience: mean difference - 0.6, p = 0.007; > 20 years experience: mean difference - 0.9, p < 0.0001). No differences were detected concerning professional background. CONCLUSIONS: CTG knowledge, interpretation skills and decision-making measured by a written assessment were positively associated with working in large maternity units and having < 15 years of obstetric work experience. This might indicate a challenge in maintaining CTG skills in small units and among experienced staff but could also reflect different levels of motivation, test familiarity and learning culture. Whether the findings are transferable to the clinical setting was not examined.

Development of a written assessment for a national interprofessional cardiotocography education program.

BACKGROUND: To reduce the incidence of hypoxic brain injuries among newborns a national cardiotocography (CTG) education program was implemented in Denmark. A multiple-choice question test was integrated as part of the program. The aim of this article was to describe and discuss the test development process and to introduce a feasible method for written test development in general. METHODS: The test development was based on the unitary approach to validity. The process involved national consensus on learning objectives, standardized item writing, pilot testing, sensitivity analyses, standard setting and evaluation of psychometric properties using Item Response Theory models. Test responses and feedback from midwives, specialists and residents in obstetrics and gynecology, and medical and midwifery students were used in the process (proofreaders n = 6, pilot test participants n = 118, CTG course participants n = 1679). RESULTS: The final test included 30 items and the passing score was established at 25 correct answers. All items fitted a loglinear Rasch model and the test was able to discriminate levels of competence. Seven items revealed differential item functioning in relation to profession and geographical regions, which means the test is not suitable for measuring differences between midwives and physicians or differences across regions. In the setting of pilot testing Cronbach's alpha equaled 0.79, whereas Cronbach's alpha equaled 0.63 in the setting of the CTG education program. This indicates a need for more items and items with a higher degree of difficulty in the test, and illuminates the importance of context when discussing validity. CONCLUSIONS: Test development is a complex and time-consuming process. The unitary approach to validity was a useful and applicable tool for development of a CTG written assessment. The process and findings supported our proposed interpretation of the assessment as measuring CTG knowledge and interpretive skills. However, for the test to function as a high-stake assessment a higher reliability is required.

Maternofetal transplacental transport of recombinant IgG antibodies lacking effector functions.

The neonatal Fc receptor (FcRn) directs the transfer of maternal immunoglobulin G (IgG) antibodies across the placenta and thus provides the fetus and newborn with passive protective humoral immunity. Pathogenic maternal IgG antibodies will also be delivered via the placenta and can cause alloimmunity, which may be lethal. A novel strategy to control pathogenic antibodies would be administration of a nondestructive IgG antibody blocking antigen binding while retaining binding to FcRn. We report on 2 human IgG3 antibodies with a hinge deletion and a C131S point mutation (IgG3ΔHinge) that eliminate complement activation and binding to all classical Fcγ receptors (FcγRs) and to C1q while binding to FcRn is retained. Additionally, 1 of the antibodies has a single point mutation in the Fc (R435H) at the binding site for FcRn (IgG3ΔHinge:R435H). We compared transplacental transport with wild-type IgG1 and IgG3, and found transport across trophoblast-derived BeWo cells and ex vivo placenta perfusions with hierarchies as follows: IgG3ΔHinge:R435H>wild-type IgG1≥IgG3ΔHinge and IgG3ΔHinge:R435H=wild-type IgG1=wild-type IgG3>>>IgG3ΔHinge, respectively. Collectively, IgG3ΔHinge:R435H was transported efficiently from the maternal to the fetal placental compartment. Thus, IgG3ΔHinge:R435H may be a good candidate for transplacental delivery of a nondestructive antibody to the fetus to combat pathogenic antibodies.

Severe and fatal obstetric injury claims in relation to labor unit volume.

OBJECTIVE: To assess possible association between the incidence of approved claims for severe and fatal obstetric injuries and delivery volume in Denmark. DESIGN AND SETTING: A nationwide panel study of labor units. POPULATION: Claimants seeking financial compensation due to injuries occurring in labor units in 1995-2012. METHODS: Exposure information regarding the annual number of deliveries per labor unit was retrieved from the Danish National Birth Register. Outcome information was retrieved from the Danish Patient Compensation Association. Exposure was categorized in delivery volume quintiles as annual volume per labor unit: (10-1377), (1378-2016), (2017-2801), (2802-3861), (3862-6659). MAIN OUTCOME MEASURES: Five primary measures of outcome were used. Incidence rate ratios of (A) Submitted claims, (B) Approved claims, (C) Approved severe injury claims (120% degree of disability), (D) Approved fatal injury claims, and (C+D) Combined. RESULTS: 1 151 734 deliveries in 51 labor units and 1872 submitted claims were included. The incidence rate ratios of approved claims overall, of approved fatal injury claims, and of approved severe and fatal injuries combined increased significantly with decreasing annual delivery volume. Face value incidence rate ratios of approved severe injuries increased with decreasing labor unit volume, but the association did not reach statistical significance. CONCLUSION: High volume labor units appear associated with fewer approved and fewer fatal injury claims compared with units with less volume. The findings support the development towards consolidation of units in Denmark. A suggested option would be to tailor obstetric patient safety initiatives according to the delivery volume of individual labor units.

Alcohol consumption and binge drinking in early pregnancy. A cross-sectional study with data from the Copenhagen Pregnancy Cohort.

BACKGROUND: Since 2007 the Danish Health and Medicines Authority has advised total alcohol abstinence from the time of trying to conceive and throughout pregnancy. The prevalence of binge drinking among pregnant Danish women has nevertheless been reported to be up to 48 % during early pregnancy. Since the introduction of the recommendation of total abstinence, no studies have examined pre-pregnancy lifestyle and reproductive risk factors associated with this behaviour in a Danish context. The aims of this study were therefore to describe the prevalence of weekly alcohol consumption and binge drinking in early pregnancy among women living in the capital of Denmark. Secondly to identify pre-pregnancy lifestyle and reproductive risk factors associated with binge drinking during early pregnancy. METHODS: Data were collected from September 2012 to August 2013 at the Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark. Self-reported information on each woman's socio-demographic characteristics, medical history, and lifestyle factors including alcohol habits was obtained from an electronic questionnaire filled out as part of the individual medical record. Descriptive analysis was conducted and multivariate logistic regression analysis was used to assess the potential associated risk factors (adjusted odds ratio (aOR)). RESULTS: Questionnaires from 3,238 women were included. A majority of 70 %, reported weekly alcohol consumption before pregnancy. The prevalence decreased to 3 % during early pregnancy. The overall proportion of women reporting binge drinking during early pregnancy was 35 % (n = 1,134). The following independent risk factors for binge drinking in early pregnancy were identified: lower degree of planned pregnancy, smoking and alcohol habits before pregnancy ((1 unit/weekly aOR 4.48, CI: 3.14 - 6.40), (2-7 units aOR 10.23, CI: 7.44-14.06), (≥8 units aOR 33.18, CI: 19.53-56.36)). Multiparity and the use of assisted reproductive technology were associated with lower odds of binge drinking in early pregnancy. CONCLUSION: The prevalence of weekly alcohol consumption decreased considerably during early pregnancy compared with pre-pregnancy levels. Nevertheless one third of the pregnant women engaged in binge drinking. Identification of risk factors for this behaviour renders it possible not only to design prevention strategies, but also to target those most at risk.

Curriculum development for a national cardiotocography education program: a Delphi survey to obtain consensus on learning objectives.

OBJECTIVE: To define learning objectives for a national cardiotocography (CTG) education program based on expert consensus. DESIGN: A three-round Delphi survey. POPULATION AND SETTING: One midwife and one obstetrician from each maternity unit in Denmark were appointed based on CTG teaching experience and clinical obstetric experience. METHODS: Following national and international guidelines, the research group determined six topics as important when using CTG: fetal physiology, equipment, indication, interpretation, clinical management, and communication/responsibility. In the first Delphi round, participants listed one to five learning objectives within the predefined topics. Responses were analyzed by a directed approach to content analysis. Phrasing was modified in accordance with Bloom's taxonomy. In the second and third Delphi rounds, participants rated each objective on a five-point relevance scale. Consensus was predefined as objectives with a mean rating value of ≥ 3. MAIN OUTCOME MEASURES: A prioritized list of CTG learning objectives. RESULTS: A total of 42 midwives and obstetricians from 21 maternity units were invited to participate, of whom 26 completed all three Delphi rounds, representing 18 maternity units. The final prioritized list included 40 objectives. The highest ranked objectives emphasized CTG interpretation and clinical management. The lowest ranked objectives emphasized fetal physiology. Mean ratings of relevance ranged from 3.15 to 5.00. CONCLUSIONS: National consensus on CTG learning objectives was achieved using the Delphi methodology. This was an initial step in developing a valid CTG education program. A prioritized list of objectives will clarify which topics to emphasize in a CTG education program.

Mode of delivery and subsequent reproductive patterns. A national follow-up study.

OBJECTIVE: To investigate associations between mode of delivery and subsequent reproductive outcomes. DESIGN: Cohort study. POPULATION: Women with term singleton live births from 1987 to 2009. SETTING: Denmark, birth registration data. METHODS: Women with a first singleton delivery after 37 weeks were followed until the end of 2010, from a first birth to include subsequent live births. We used Cox's proportional hazards model stratified by parity to compare the likelihood for subsequent delivery according to mode of delivery at first and later births, estimating maternal age effects and lag time to next delivery. MAIN OUTCOME MEASURE: Likelihood of a subsequent live-born child by previous delivery mode. RESULTS: We identified 642,052 women with a first delivery. Compared with women with a non-instrumental vaginal delivery, delivering a child by elective cesarean section implied a 23% (95% CI 0.76-0.787) decreased likelihood for subsequent delivery. Emergency cesarean section meant 16% fewer (95% CI 0.84-0.85), and vaginal instrumental delivery 4% fewer subsequent deliveries (95% CI 0.95-0.96). Hazard ratios were largely unchanged after controlling for parity and year of birth. Small age-trends were seen, with hazard ratios affected by maternal age at birth. Delivery mode at first birth affected marginally the time lag until next birth. CONCLUSIONS: Fecundity, measured as likelihood of a successive live-born child, varied with mode of delivery at the first and also subsequent births. A first or later delivery by cesarean section implied decreased likelihood of subsequent delivery compared with women with a first vaginal birth.

Next-generation sequencing: proof of concept for antenatal prediction of the fetal Kell blood group phenotype from cell-free fetal DNA in maternal plasma.

BACKGROUND: Maternal immunization against KEL1 of the Kell blood group system can have serious adverse consequences for the fetus as well as the newborn baby. Therefore, it is important to determine the phenotype of the fetus to predict whether it is at risk. We present data that show the feasibility of predicting the fetal KEL1 phenotype using next-generation sequencing (NGS) technology. STUDY DESIGN AND METHODS: The KEL1/2 single-nucleotide polymorphism was polymerase chain reaction (PCR) amplified with one adjoining base, and the PCR product was sequenced using a genome analyzer (GAIIx, Illumina); several millions of PCR sequences were analyzed. RESULTS: The results demonstrated the feasibility of diagnosing the fetal KEL1 or KEL2 blood group from cell-free DNA purified from maternal plasma. CONCLUSION: This method requires only one primer pair, and the large amount of sequence information obtained allows well for statistical analysis of the data. This general approach can be integrated into current laboratory practice and has numerous applications. Besides DNA-based predictions of blood group phenotypes, platelet phenotypes, or sickle cell anemia, and the determination of zygosity, various conditions of chimerism could also be examined using this approach. To our knowledge, this is the first report focused on antenatal blood group determination using NGS.

The size of the labor wards: is bigger better when it comes to patient safety?

OBJECTIVE: To assess possible associations between the size of labor units and the frequency of approved obstetric claims. DESIGN: A nationwide retrospective descriptive study. SETTING: Denmark. POPULATION: All patients seeking financial compensation due to obstetric injuries occurring between 1995 and 2009. METHODS: In all, 1440 anonymized obstetrics claims were reviewed; 1326 were included in the study. Information regarding the annual number of deliveries for each place of injury was retrieved from the National Birth Registry. MAIN OUTCOME MEASURES: Obstetric injuries approved by the Danish Patient Insurance Association categorized by labor unit size. RESULTS: The overall approval rate for submitted claims was 39.7%. Large labor units (3000-3999 deliveries/year) were found to have a lower approval rate (34.2%), compared with very large (≥4000 deliveries/year, 38.6%), intermediate (1000-2999 deliveries/year, 41.7%), and small (<1000 deliveries/year, 50.0%) units, (p < 0.05). The majority of compensation claims were approved with reference to the "specialist rule," assuming that if an experienced specialist had conducted the treatment differently the injury could have been avoided. Claims from small units showed a trend for being more often based on the specialist rule than seen in larger units (p < 0.05, test for trend). CONCLUSION: The results may reflect that large labor units are living up to the principle of best practice to a greater degree. Several factors can be linked to the size of the labor unit and a better availability of in-house obstetricians as well as auxiliary specialists could be part of the explanation.

Pregnant woman with fatal complication after laparoscopic Roux-en-Y gastric bypass.

In Europe, an increasing number of women have bariatric surgery; therefore, obstetricians are likely to encounter these patients. We report a 22-year-old woman, who had previously undergone uncomplicated laparoscopic Roux-en-Y gastric bypass. She was admitted with severe abdominal pain at 35 weeks of gestation. A cesarean section with delivery of a healthy baby in combination with an exploratory laparotomy was performed. Internal herniation was suspected, but not identified during surgery. Three days later she died of a severely gangrenous small bowel secondary to internal herniation. This fatal case illustrates a potential complication and difficulties in the management of pregnant women who have undergone Roux-en-Y gastric bypass. In these women, observation and investigations based on a multidisciplinary approach are vital if abdominal pain develops, with involvement of intestinal surgeons experienced in bariatric surgery, as well as radiologists with specific knowledge of relevant imaging procedures.

A group B Streptococcus alpha-like protein subunit vaccine induces functionally active antibodies in humans targeting homotypic and heterotypic strains.

Maternal vaccination is a promising strategy for preventing neonatal disease caused by group B Streptococcus. The safety and immunogenicity of the prototype vaccine GBS-NN, a fusion protein consisting of the N-terminal domains of the alpha-like proteins (Alp) αC and Rib, were recently evaluated favorably in healthy adult women in a phase 1 trial. Here we demonstrate robust immunoglobulin G (IgG) and immunoglobulin A (IgA) responses against αC and Rib, as well as against the heterotypic Alp family members Alp1-Alp3. IgA and heterotypic IgG responses are more variable between subjects and correlate with pre-existing immunity. Vaccine-induced IgG mediates opsonophagocytic killing and prevents bacterial invasion of epithelial cells. Like the vaccine-induced response, naturally acquired IgG against the vaccine domains is dominated by IgG1. Consistent with the high IgG1 cross-placental transfer rate, naturally acquired IgG against both domains reaches higher concentrations in neonatal than maternal blood, as assessed in a separate group of non-vaccinated pregnant women and their babies.

Sports and leisure time physical activity during pregnancy in nulliparous women.

To describe patterns of leisure time physical activity during pregnancy in relation to pre-pregnancy leisure time physical activity, socio-demographic characteristics, fertility history, and lifestyle factors. 4,718 nulliparous with singleton pregnancy and intended spontaneous vaginal delivery were included in the study at gestational week 33 from May 2004 to July 2005. Information was provided by self-administered questionnaires. Leisure time physical activity was categorised into four categories: competitive sport, moderate-to-heavy, light or sedentary. In this population of nulliparous women, 4% participated in competitive sport, 25% in moderate-to-heavy activities, 66% in light activities, and 5% in sedentary activities in the year prior to pregnancy. Physical activity before pregnancy was statistically significantly associated with age, pre-pregnancy BMI, chronic diseases, number of years at school, and smoking habits. The proportion of women who took part in competitive sports, and moderate-to-heavy activities decreased over the three trimesters of pregnancy. The proportion of women with light physical activity was stable during pregnancy while the proportion of women with sedentary activity increased from 6% to 29%. During the third trimester women performing competitive sports or moderate-to-heavy activities before pregnancy continued to have a higher level of physical activity than women with light activities or sedentary activities before pregnancy. In general the intensity and time spent on exercise decreased during pregnancy. Women with the highest level of exercise prior to pregnancy continued to be the most active during pregnancy. Among women with sedentary activities before pregnancy one-fourth changed to light activity during pregnancy.

Can a 15-mm cervical length cutoff discriminate between low and high risk of preterm delivery in women with threatened preterm labor?

OBJECTIVES: To investigate if a cervical length (CL) cutoff of 15 mm is relevant to use in women with threatened preterm labor. METHODS: From 2006 to 2009, 146 women with singleton pregnancies were admitted with threatened preterm labor between 23 and 33+6 weeks of gestation at Copenhagen University Hospital. Transvaginal sonographic measurement of CL was carried out on admission. Outcome measures were spontaneous delivery within 48 h, within 7 days and delivery before 34 weeks according to a CL cutoff of 15 mm. RESULTS: CL was <15 mm in 36 women (24.7%) and ≥15 mm in 110 women (75.3%). Spontaneous delivery occurred within 48 h or 7 days of presentation and before 34 weeks in 25, 38.9 and 50.0% of women with CL <15 mm and 3.6, 9.1 and 11.8% of women with CL ≥15 mm, respectively. The 15-mm CL cutoff had a sensitivity, false positive rate and negative predictive value for delivery within 48 h of 69.0, 20.3 and 96.4%, and within 7 days of 58.3, 18.1 and 90.9%. Women with CL <15 mm had odds of delivery within 7 days of 6.4 (95% CI 2.5-16.2). CONCLUSION: Although a 15-mm CL defines a group of women at high risk of spontaneous preterm delivery, 10 out of 110 women (9.1%) with a CL ≥15 mm deliver within 7 days.

Intrapartum transfer of oxytocin across the human placenta: An ex vivo perfusion experiment.

INTRODUCTION: Investigation of the maternal to fetal transfer of oxytocin across the dually perfused term human placenta. METHODS: Human placentae obtained from term singleton pregnancies were utilized in a dual recirculating model of ex vivo placental perfusion. Six placentae from women delivering by elective cesarean at term were perfused, one blank and five with the test substance synthetic oxytocin (0.8 ng/mL) (OX) added to the maternal perfusate for 180 min. Antipyrine was used as positive control to validate overlap of the maternal and fetal circuits. The concentration of OX was determined by radioimmunoassay. RESULTS: A fall in maternal concentration of OX was seen throughout the experiment. At 90 min of perfusion a state of equilibrium was reached between maternal and fetal concentrations; however after 180 min the fetal concentration of OX was higher than that of the maternal. 31 % of the test substance was accounted for at the end of the experiment - suggesting OX protein binding and a high degree of oxytocinase activity. DISCUSSION: The ex vivo perfusion experiments revealed low transfer of OX to the fetal circuit below physiologically relevant concentrations.