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The cervix maintains the fetus in situ during pregnancy and dilates during labour to allow delivery of the baby. Congenital or iatrogenically-induced structural abnormalities of the cervix are associated with an increased risk of preterm birth. The role of cervical infection is less clear. Cervical studies may be useful in the prediction of preterm delivery: both a shortened cervical length identified on transvaginal ultrasound examination and an increased level of fetal fibronectin in cervico-vaginal secretions are associated with an increased risk of preterm delivery. In singleton pregnancy, cervical cerclage reduces the risk of preterm birth by 25%. There is no evidence of a reduction in neonatal mortality or morbidity, and the beneficial effects of preterm birth reduction have to be set against the increased risk of maternal infection. Neither the American College of Obstetricians and Gynecologists (ACOG) nor the Royal College of Obstetricians and Gynaecologists (RCOG) has unequivocally endorsed cervical cerclage. Further work is required to define the role of the cervix in prediction and prevention of spontaneous preterm birth.

A subsample of 681 women participating in a two-centred, three-setting larger (2817) prevalence study were approached and, with consent, administered a questionnaire by post or in person. The questionnaire asked about their views of opportunistic screening for Chlamydia trachomatis (CT). The study response rate was 71%. In all, 94% women reported screening should be offered and most, on a regular basis. About 91% thought men should be screened but only 47% thought they would attend. Most (89%) knew the term 'chlamydia' but fewer, (63%) knew they could catch CT more than once. This is one of the very few UK studies which has explored women's views towards the acceptability of CT screening. Results suggest the majority of women report that screening for the condition is acceptable but not all have in-depth knowledge of CT. If a screening programme is to be established more education regarding the condition is required.

Results: Co-culture of explants with T cells results in a trend towards reduced system A activity. Syncytial function, assessed by hCG production, was unaffected by culture with immune cells. Therewasno systematic effect of culturing explantswith cytokines. Discussion: Immune cells in the placental environment may have a detrimental effect on the nutrient transport capabilities of the organ as demonstrated by a reduction in system A activity. Culture with cytokines alone does not demonstrate the same effect, implying that an inflammatory milieu is required. Further work is required to fully assess the effect of the culture environment on cell turnover and hormone production.

INTRODUCTION: Increasing evidence suggests obesity has its origins prior to birth. There is clear correlation between maternal obesity, high birthweight and offspring risk of obesity in later life. It is also clear that women who are obese during pregnancy are at greater risk of adverse outcomes, including gestational diabetes and stillbirth. The mechanism(s) by which obesity causes these problems is unknown, although hyperglycaemia and insulin resistance are strongly implicated. We present a protocol for a study to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high birthweight babies and other pregnancy complications.METHODS AND ANALYSIS: The Efficacy of Metformin in Pregnant Obese Women, a Randomised controlled (EMPOWaR) trial is a double-masked randomised placebo-controlled trial to determine whether metformin given to obese (body mass index >30 kg/m(2)) pregnant women from 16 weeks' gestation until delivery reduces the incidence of high birthweight babies. A secondary aim is to test the mechanism(s) of any effect. Obese women with a singleton pregnancy and normal glucose tolerance will be recruited prior to 16 weeks' gestation and prescribed study medication, metformin or placebo, to be taken until delivery. Further study visits will occur at 28 and 36 weeks' gestation for glucose tolerance testing and to record anthropometric measurements. Birth weight and other measurements will be recorded at time of delivery. Anthropometry of mother and baby will be performed at 3 months postdelivery. As of January 2014, 449 women had been randomised across the UK.ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles of Good Clinical Practice. A favourable ethical opinion was obtained from Scotland A Research Ethics Committee, reference number 10/MRE00/12. Results will be disseminated at conferences and published in peer-reviewed journals.TRIAL REGISTRATION NUMBER: ISRCTN51279843.

The region of fetal membranes overlying the cervix, known as the zone of altered morphology (ZAM), is considered to be the principle site of membrane inflammatory activity and extracellular matrix remodelling. We wished to quantify the relative contribution of each area of fetal membranes to the inflammatory process of parturition. Specifically, we aimed to quantify and compare (1) leukocyte densities in three regions of fetal membranes and decidua before and during spontaneous labor at term, and (2) mRNA expression of interleukin (IL)-1β, IL-6, IL-8, cy do-oxygenase type 1 (COX-1), and COX-2 in three regions of fetal membranes and decidua before and during spontaneous labor at term. Biopsies of fetal membranes and decidua were obtained from pregnant women delivered by cesarean section at term both before and during spontaneous labor (n = 8 both groups). Fetal membranes were sampled from three areas, the ZAM, midzone (MZ), and periplacental (PP) regions. Leukocytes were identified by immunohistochemistry and their density quantified. Inflammatory mediator expression was quantified using TaqMan technology (Applied Biosystems, Foster City, CA). There was a significantly greater density of leukocytes in (1) the PP region of membranes compared with the ZAM, and (2) the decidua compared with amnion, amniotic connective tissue, and chorion. IL-1β, IL-6, and IL-8 mRNA expression was significantly greater in all regions following spontaneous labor compared with nonlaboring tissues. There were no regional differences in cytokine expression within the fetal membranes. Choriodecidua expressed significantly more IL-1β mRNA than amnion. Amnion expressed more COX-2 mRNA than choriodecidua. All regions of fetal membranes and decidua contribute to the inflammatory process of human parturition; however, their relative contributions differ in magnitude. Although the ZAM may be specifically important for membrane rupture, it does not appear to play a key or exclusive role in the other inflammatory processes of parturition. When studying fetal membranes, it is relevant to identify and define the area sampled for consistency and comparison with other studies. (J Soc Gynecol Investig 2006;13: 97—103) Copyright © 2006 by the Society for Gynecologic Investigation.

Preterm birth remains a major contributor to perinatal death in both resource-poor and resource-rich countries, with about 35% of deaths in the first four weeks of life directly attributable to prematurity. This article examines the reasons why preterm birth is so difficult to treat.

There is increasing evidence to support the view that human parturition represents an inflammatory process. We have previously demonstrated that parturition is associated with leukocyte invasion and pro-inflammatory cytokine production in the cervix and myometrium. Furthermore, we have shown that several cell adhesion molecules are upregulated in these tissues during labor. In fetal membranes, previous studies have shown intercellular adhesion molecule-1 (ICAM-1) upregulation in association with labor. The role of other adhesion molecules has not been explored. The aims of this study were, therefore, to determine the expression of ICAM-1, platelet endothelial cell adhesion molecule (PECAM), vascular cell adhesion molecule (VCAM) and E-selectin in pre- and post-laboring amnion and choriodecidua and to identify cell types responsible for their expression. Biopsies of fetal membranes were obtained from pregnant women delivered by caesarean section before the onset of labor (n = 8) and following spontaneous vaginal delivery (n = 8). Cell adhesion molecules were identified using immunohistochemistry and messenger RNA expression quantified using Northern analysis. We found that following labor, ICAM-1 mRNA expression was significantly upregulated in amnion and choriodecidua (P0.05). PECAM mRNA expression was also increased in choriodecidua (P0.05). The main cell types responsible for adhesion molecule expression were leukocytes, amniotic epithelial cells and endothelial cells. The upregulation of ICAM-1 and PECAM mRNA expression in fetal membranes following labor provides further evidence that fetal membranes play an important role in the inflammatory process of parturition.

Objective Assessment of ovarian responses to metformin treatment in obese women with polycystic ovary syndrome (PCOS). Design Prospective treatment with randomization to two doses of metformin. Setting University teaching hospital. Patient(s) Obese women (n = 82) with PCOS. Intervention(s) Markers of ovarian function were assessed after 4 and 8 months. Main outcome measure(s) Hormone (androgens and mullerian-inhibiting substance [MIS]) changes over time. Result(s) There was no difference in the reproductive hormone changes between the doses of metformin, and data were combined for further analyses. Significant responses to treatment were recorded for menstrual frequency and androstenedione (A) (reduction) within the first 4 months of treatment. However, suppression of the elevated circulating MIS concentrations required protracted treatment, because no change was observed in the first 4 months—only in the second 4-month assessment period. Conclusion(s) Metformin treatment of PCOS leads to rapid suppression of A and improved menstrual frequency. Suppression of MIS is a delayed response that may be secondary to the development of a cohort of follicles that underwent initial recruitment in an environment of reduced insulin stimulation.

Hirsutism is a common and distressing symptom frequently encountered in women with polycystic ovary syndrome (PCOS), who also show relative insulin resistance. The aim of this trial, in which hirsutism was the primary end point, was to compare the efficacy of the oral antihyperglycemic medication metformin with that of an established treatment, combined ethinyl estradiol and cyproterone acetate. Patients (n = 52) were randomized to receive either metformin (500 mg, three times daily) or Dianette (ethinyl estradiol, 35 micro g; cyproterone acetate, 2 mg) treatment for 12 months, with assessments before treatment, at 6 months, and at 12 months. Both objective and subjective methods of evaluating hirsutism were used, and in addition, patient perceptions were examined. The results show that metformin is potentially an effective treatment for moderate to severe hirsutism in women with PCOS. They also suggest that in some respects (Ferriman-Gallwey score and patient self-assessment), it is more efficacious than the standard treatment (Dianette). The objective evaluation of hair diameter reduction showed that both treatments were moderately effective at multiple anatomical sites. Dianette treatment was responsible for profound suppression of androgen activity, in contrast to metformin, which induced negligible change. However, metformin did reduce markers of insulin resistance. The data suggest that hirsutism may be effectively treated by reducing hyperinsulinemia.

Vaginally administered nitric oxide donors such as isosorbide mononitrate have been used to ripen the uterine cervix in pregnancy. The pharmacokinetics of isosorbide mononitrate following vaginal administration are unknown. Serum levels of isosorbide mononitrate were determined at baseline and 60, 180 and 360 minutes after vaginal administration of 20 or 40 mg isosorbide mononitrate to pregnant women scheduled for induction of labour at term. Serum levels of isosorbide mononitrate continued to rise up to 360 minutes after isosorbide mononitrate insertion, with mean (SD) final levels of 337 (94) microg/L following isosorbide mononitrate 40 mg and 144 (47) microg/L following isosorbide mononitrate 20 mg, P0.01.

Background. Accidental out-of-hospital (OHD) deliveries are associated with high rates of perinatal morbidity and mortality. The ability of health care workers to identify women at risk of out-of-hospital delivery is limited. The purpose of this study was to determine the prevalence of these deliveries in our population and to quantify the neonatal morbidity and mortality associated with such births. Further we aimed to determine whether women at risk of accidental out-of-hospital delivery in our population could be identified antenatally. Methods. A retrospective case-control study was performed. Women who delivered accidentally out-of-hospital in our catchment area between January 1995 and March 1999 were identified (cases) and compared with women who delivered in hospital following spontaneous labor (controls). Outcome measures included maternal demographic characteristics, obstetric features and neonatal outcome. Results. In the study period, 117 women delivering 121 babies were identified who delivered accidentally out-of-hospital, (0.6% of all deliveries registered at the hospital). Women who delivered before arrival at hospital were more likely to be of greater parity, unbooked, late bookers and/or poor attenders for antenatal care. Gestation at delivery, duration of labor and birthweight were less in the out-of-hospital delivery group compared with the control group. The rate of perineal suturing was lower for cases than controls. Babies who were delivered accidentally out-of-hospital were more likely to require admission to the neonatal unit and had a higher perinatal mortality rate than controls (51.7 versus 8.6/1000 deliveries, respectively). Conclusions. Accidental out-of-hospital deliveries account for less than 1% of deliveries in our population, but are associated with significant perinatal morbidity and mortality. Women should be educated regarding the importance of both antenatal care and a planned delivery. Since the majority of women who deliver accidentally out-of hospital are parous, there is an opportunity to do this in a previous confinement.

Each of the proinflammatory cytokines interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor (TNF) alpha has been identified in reproductive tissues during labor. The cellular origin of these cytokines is unclear. The aim of this study was to localize these proinflammatory cytokines in myometrium (upper and lower segment), cervix, and fetal membranes at term. Biopsies were taken from women undergoing cesarean section either before or after the onset of labor. Immunohistochemistry was used to localize each of the cytokines IL-1beta, IL-6, IL-8, and TNFalpha. Leukocytes were localized using an antibody to CD45. In myometrium and cervix, immunostaining for IL-1beta was predominantly in leukocytes. In fetal membranes, IL-1beta localized to leukocytes and to the stromal cells of the decidua. In myometrium, IL-6, IL-8, and TNFalpha were restricted to leukocytes, which were present in greater numbers in tissue obtained during labor. In cervix, IL-6, IL-8, and TNFalpha localized to leukocytes and glandular and surface epithelium. IL-8 also localized to cervical stromal cells. In fetal membranes, IL-6 and TNFalpha were expressed by decidual stromal cells, infiltrating leukocytes, and extravillous trophoblasts. In membranes, IL-8 localized to leukocytes in the chorion but was not detected in the amnion. In fetal membranes collected at labor, IL-8 was expressed in decidual stromal cells. Infiltrating leukocytes are a major source of cytokines in uterine tissues during labor.

Spontaneous preterm delivery is an important cause of neonatal morbidity and mortality, but there is little consensus on the best way to manage women with signs and symptoms of preterm labour. We conducted a survey of all 198 consultant-led maternity units in the UK to establish management of women presenting with threatened preterm labour (April–July, 2014). We contacted a consultant obstetrician in each unit (labour ward lead consultant, preterm labour special interest consultant or clinical director) and asked them, or a deputy, to complete an online survey about their hospital protocols. Consultants from 133 of 198 (67.2%) consultant-led obstetrics units responded: 59.4% (79/133) with neonatal intensive care facilities, 21.1% (28/133) with high dependency facilities and 19.5% (26/133) with special care facilities. There were 126/133 (94.7%) units that used one or more …

Introduction Protease-activated receptor 4 (PAR4) is expressed widely in haemopoietic and vascular tissues and mediates thrombin-induced platelet activation primarily through Gq, protein kinase C and Ca2+ dependent pathways. Platelet PAR4 function may be modified by common non-coding variants near F2RL3 which encodes PAR4, and by epigenetic regulators which affect F2RL3 expression. However, coding sequence variants which affect PAR4 expression or function have not been reported previously. Here we characterise a novel missense variant in F2RL3associated with loss of PAR4 function in platelets from heterozygous subjects and reduced surface expression in platelets and a cell model. Methods The index case (P1) was identified by re-sequencing platelet G-protein coupled receptor genes in sub-groups of a collection of 2,400 adult cardiac surgery patients (GRAPHICS study; UK REC 12/SW/0286). Platelets were studied by light transmission aggregation (LTA) and by measuring P-selectin exposure, PAC-1 binding and intracellular Ca2+mobilisation in response to activating agonists. Platelet PAR4 expression was measured in platelets by flow cytometry and immunoblot and in transiently transfected HEK293 cells by flow cytometry and fluorescence microscopy. Results P1 was a 66 year old male with lifelong mild mucocutaneous bleeding and two gastrointestinal bleeds during aspirin treatment who harboured a heterozygous c.471A>G transition in F2RL3predicting a p.Tyr157Cys (Y157C) substitution in PAR4. Platelet phenotype Compared to healthy controls, platelets from P1 showed reduced aggregation responses to the PAR4 agonist AYPGKF (60-600 μM; EC50 P1 266 μM vs controls 153 μM (n=11)) and to α-thrombin (5-100 mU.ml-1; EC50 P1 51 mU.ml-1 vs controls 15 mU.ml-1 (n=8)) with the greatest reduction in responses at 150 μM AYPGKF (maximum amplitude (MA) P1 1% vs controls 56%; p The c.471A>G F2RL3 variant was identified in two sons of P1, who also showed reduced platelet functional responses to AYPGKF and PAR4 surface expression that were similar to P1, indicating co-segregation of platelet phenotype and the variant F2LR3 genotype. However, these subjects did not display abnormal bleeding. Y157C PAR4 in HEK293 cells Variant PAR4 with a C-terminal CFP tag (Y157C PAR4-CFP) expressed in HEK293 cells showed reduced surface expression by flow cytometry (mean of median fluorescence intensities 28% that of wild-type (WT) PAR4-CFP with SEM 5%; n=3). Consistent with this, fluorescence microscopy revealed predominantly intracellular expression of Y157C PAR4-CFP in the HEK293 cells with limited cell surface expression when compared to WT PAR4-CFP. Conclusion The Y157 residue is highly conserved within transmembrane domain 3 of PAR4 that, in other G protein coupled receptors, is crucial for maintaining normal receptor structure. Therefore, the Y157C substitution identified in the index case in PAR4 is likely to adversely affect receptor function. Consistent with this, our data from multiple functional assays show reduced platelet responses to α-thrombin and to a PAR4 specific agonist, but not to a PAR1 specific agonist. This platelet phenotype co-segregated with the heterozygous Y157C substitution in the study kindred suggesting a causal association. However, this was not associated with bleeding in all kindred members. In both platelets and HEK293 cells we demonstrated the Y157C substitution was associated with loss of PAR4 function and reduced surface receptor expression. This is the first description of a missense PAR4 variant causing loss of receptor function as a heritable trait. Disclosures No relevant conflicts of interest to declare.

The hypothalamic-pituitary-adrenal (HPA) axis is important for fetal growth and timing of parturition. Maternal obesity is associated with macrosomia (birthweight ⩾4000g) and prolonged pregnancy (⩾41weeks). We aimed to characterise HPA axis hormones in obese pregnancy and to test associations with these pregnancy outcomes.Fasting cortisol was measured by radioimmunoassay in venous blood at 16, 28 and 36 weeks of gestation in 286 obese (BMI 44.05±3.98kg/m(2)) and 137 lean (BMI 22.71±1.66kg/m(2)) pregnant women. In subsets (n=20 obese, 20 lean) we measured corticosteroid binding globulin (CBG) and CRH by radioimmunoassay; progesterone, estradiol (E2), estriol (E3) and sex-hormone-binding-globulin (SHBG) by ELISA; and albumin by bromocresol green binding. Free cortisol levels were calculated using Coolen's equation.Cortisol, CBG, calculated free cortisol, CRH, E2, E3, progesterone and SHBG levels rose similarly during pregnancy in obese and lean, but were significantly lower in obese (p0.05). In obese, lower free cortisol at 16 weeks was associated with higher birthweight (r=-0.46, p0.05). Cortisol was not associated with labour onset. CRH was significantly lower at 36 weeks in women who delivered at ⩾41weeks and in women with macrosomic babies (p0.05); and correlated negatively with gestation at delivery in obese (r=-0.557, p0.05).Our findings suggest that decreased HPA axis activity in obese pregnancy may be a mechanism underlying macrosomia and prolonged pregnancy.

Background Increased hypothalamic-pituitary-adrenal (HPA) axis activity has been associated with low birthweight and preterm labour. Maternal obesity is associated with macrosomia (birthweight ≥4000 g) and prolonged pregnancy (≥41 weeks). We hypothesised altered HPA axis activity may underlie these pregnancy outcomes and aimed to characterise HPA axis hormones in obese pregnancy. Method Fasting serum cortisol was measured by radioimmunoassay at 16, 28 and 36 weeks in 286 obese (BMI 44.05 ± 3.98 kg/m 2 ) and 137 lean (BMI 22.71 ± 1.66 kg/m 2 ) pregnant women. In subsets (n = 20 obese, 20 lean) we measured corticosteroid-binding-globulin (CBG) and corticotrophin-releasing-hormone (CRH) by radioimmunoassay. Free cortisol was calculated using Coolen’s equation. Results Cortisol was significantly lower throughout pregnancy in obese (Table 1), and lower free cortisol at 16 weeks was associated with higher birthweight (r = -0.46, p Conclusion Decreased HPA axis activity in obese pregnancy may underlie macrosomia and prolonged pregnancy.

Maintenance of uterine quiescence is critical for maintenance of pregnancy and prevention of preterm birth. Progesterone and other sex steroids appear to relax the myometrium but the mechanism of action is unknown. We sought to a) quantify stretch-induced contractions of human and mouse myometrium in vitro following exposure to a variety of sex steroids including Dihydrotestosterone (DHT), Testosterone (T), Estradiol (E2) and Progesterone (P4) and b) examine whether the effect is hormone specific or a generic steroid effect. Myometrial biopsies were obtained from non-labouring women at term and from non-pregnant C57BL/6 mice. Contraction parameters of myometrium under tension were quantified prior to and post-treatment with either each hormone separately (10 μΜ–100 μM) or a “cocktail”, consisting of 10 μM of each. In human, 100 μΜ of steroid decreased amplitude of contractions to 3.7 ± 2.4% of baseline for DHT, 9.7 ± 2.7% of baseline for T, 1.7 ± 1.7% of baseline for E2 and 21 ± 13.1% of baseline for P4 (n = 7, p

Introduction Fetal fibronectin (fFN) is a leading predictor of spontaneous preterm birth (sPTB) in high-risk asymptomatic women. As a positive/negative test (threshold of 50 ng/mL) the negative predictive value is high but positive predictive value (PPV) modest. The EQUIPP study aimed to determine if quantitative analysis of fFN (qfFn) improved prediction. Methods A prospective masked observational study (n = 1387) of high-risk asymptomatic women who underwent qfFN testing between 22 +0 – 27 +6 weeks’ gestation at 5 UK centres. Primary endpoint: sPTB Results sPTB rate Conclusion qfFN provides alternative thresholds to define risk of sPTB compared with qualitative assessment. For high-risk women with qfFN

Rates of caesarean section (CS) continue to rise in the UK. CS on maternal request is now endorsed by NICE, with NICE emphasising the importance of informed decision-making. The short-term consequences of CS for mother and baby are summarized in the NICE guideline on caesarean section. However, the long-term consequences of CS are less frequently discussed with women. We searched Medline, Embase, Cochrane and Google Scholar databases for randomised controlled trials and prospective cohort studies comparing childhood outcomes following primary CS and vaginal delivery. Additional studies were identified from reference lists of relevant papers. We restricted inclusion to studies of 1000 or more participants and with follow-up of greater than one year. The quality of studies was assessed using SIGN criteria. RevMan was used to compile data and construct a meta-analysis. We identified 13 papers which included around 250 000 babies delivered by CS. Odds ratios for specific childhood outcomes are displayed in the table below. Summary Babies delivered by CS have an increased risk of asthma, wheeze and obesity during childhood. This information should be valuable in helping pregnant women make informed choices about mode of delivery.

Background Eye-tracking has provided new insights into the development of infant cognition and is currently being explored as a potential way to identify early biomarkers of later difficulty. We aimed to assess social cognitive ability across levels of stimulus complexity in infancy. Methods Participants were 32 typically-developing (TD) infants aged 6–12 months, recruited with ethical approval (from University of Edinburgh). We measured 3 aspects of social cognition using stimuli of increasing complexity: attention distributed across faces; attention to faces in a grid-like array; and attention to faces embedded in naturalistic scenes. Results In each task we found evidence of longer fixation duration on socially informative content compared with other regions (i.e. eyes versus mouths, faces versus other objects; Wilcoxon signed-ranks all p Conclusions Each task showed evidence of infant interest in social information. Evidence from first fixation data reveals that these social preferences are mediated by stimulus complexity. Caution must therefore be taken when examining early biomarkers in social cognition because stimulus complexity may influence infants’ capacity to demonstrate social attentional preferences. These findings have implications for development of eye-tracking tasks as biomarkers of later difficulty.

Introduction In-utero substance exposure is associated with increased risk of infant neurodevelopment impairment. We measured fetal brain volume and surface area in the 3 rd trimester using 3T MRI to investigate: (1) performance of a fetal motion correction algorithm; (2) effect of maternal substance misuse (methodone, diazepam, trazadone). Methods Three sets of HASTE acquisitions were acquired in each of axial, sagittal and coronal planes in 46 pregnant women at 36–38 weeks’ gestation. Images were motion-corrected and reconstructed to form a single 3D high-resolution brain image for each fetus. 1 Motion-corrected data was rated based on image quality: best (A), good (B), moderate (C), poor (D), reconstruction failed (E). Resulting 3D-datasets with A–C were used to estimate fetal brain intracranial (whole brain including cerebrospinal fluid), cerebellum and cerebrum volumes, and cerebral hemisphere and cerebellum surface areas using stereology methods (Isotropic Cavalieri). 2 All measures were adjusted for gestational age at scan, birthweight and gender. Results After motion correction, 36 (78%) datasets met the criteria for subsequent morphological measurements. Intracranial volume (p = 0.011) and cerebral volume (p = 0.017) were significantly lower in fetuses exposed to maternal substance misuse. Discussion Quality of motion-corrected data depends greatly on degree of fetal motion. In particular gyri and sulci may still not be clearly depicted on the reconstructed 3D image. Imaging earlier in pregnancy may be informative at determining the gestation of fetal brain vulnerability to maternal substance misuse. References Kim K, et al. IEEE Trans. Med. Imaging. 2010; 29( 1): 146–158 Cruz-Orive LM, et al. J Microsc. 2010;240(2):94–110

Background Current diagnostic tests for uteroplacental insufficiency are limited. Glutamine and glutamate (Glx) play a vital role in the production of the nucleotides and amino sugars required for cell proliferation in the placenta. Choline (Cho) is a marker of cell turn-over. Proton spectroscopy magnetic resonance spectroscopy ( 1 H MRS) is a safe, non-invasive imaging technique which can detect Glx and Cho. We hypothesised that placenta Glx:Cho ratio could be a useful biomarker of placental function in pregnancies complicated by FGR. Objective To undertake a proof-of-concept study assessing placental Glx:Cho ratio in women with healthy pregnancies compared to suspected FGR. Study design In vivo placental 1 H MRS was performed in 7 pregnancies with FGR and matched to healthy controls. MRI placental volumes were measured. Oxygenation and acid-base balance were determined at birth where possible. Results Figure 1 demonstrates an exemplar spectra. The Glx:Cho ratios are shown in Table 1. In each case the Glx/Cho ratio for the FGR placentas are lower than in that of their matched control (p Conclusion This preliminary study demonstrates that Glx/Cho ratio may be a potential biomarker of placental insufficiency. Future studies need to establish normal ranges for gestation and explore the clinical implication of a low Glx/Cho ratio for perinatal outcome.

Background The diagnosis of aneuploidies via the detection of circulating fetal DNA from maternal circulation is impaired by low fetal fractions i.e. concentration of fetal DNA relatively to maternal DNA. Low fetal fractions (FF) result from poor sample management (sample collection procedures, delays in plasma extraction) or biological factors such as obesity. To alleviate sample rejection due to these factors we propose a microfluidic device capable of on-site enrichment of FF directly from maternal blood sample. Method This device simultaneously collects plasma and enriches FF from maternal DNA background via size-fractionation in an efficient single-step sample preparation process. Plasma from 8 male bearing patient blood samples was recovered from the microfluidic chips and centrifugation controls. Circulating DNA was purified for each sample series. qPCR amplification of male fetal DNA target DYS14 and a universal target, β-actin was used to quantify fetal DNA levels in the samples from patient bearing a male fetus. Findings The microfluidic extraction resulted in a 3.5 fold average relative increase of FF relatively to the centrifugation control (p = 0.01, Student’s t-test). In plasma extracted through the microfluidic chip, the FF range was found to be 11.26–68.15% with a mean of 37.66% while centrifugation resulted in FF range of 0.06–25% with a mean of 10.73%. Conclusion This device significantly enriches fetal DNA fractions from maternal blood without the need for expensive apparatus. It could be deployed near-patient to improve the recovery of fetal DNA, aneuploidy testing accuracy, and the ability to test NIPT samples with low fetal fractions.

Introduction One in five women in the United Kingdom is obese at antenatal booking. We aimed to determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in later life. Methods Maternity records of women who gave birth to their first child between 1950 and 1976 (n = 18,912) from the Aberdeen Maternity and Neonatal databank were linked to the General Register of Deaths, Scotland and the Scottish Morbidity Record systems. Death and hospital admissions for cardiovascular events up to 1 January 2012 were recorded with median follow-up of 50 years. Maternal body mass index (BMI) was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on outcomes was tested with time to event analysis with Cox proportional hazard regression to compare outcomes of mothers in underweight, overweight, or obese categories of BMI as recommended by WHO compared to mothers with normal BMI. Results All-cause mortality was increased in obese mothers (BMI >30kg/m 2 ) compared with mothers with normal BMI after adjustment for maternal age at delivery, socioeconomic status, smoking status, gestational age at BMI measurement, pre-eclampsia and low birth weight (hazard ratio 1.35, 95% CI: 1.02–1.78). In adjusted models, overweight and obese mothers have increased risk of major cardiovascular events, MACE (1.12, 1.01–1.24 and 1.37, 1.07–1.75 respectively) and hospital admission for a cardiovascular event (1.27, 1.16–1.39 and 1.49, 1.19–1.86) compared to mothers with normal BMI. Underweight mothers also had increased risk of MACE (1.21, 1.00–1.45), suggesting a possible J-shaped relationship. Conclusions Maternal obesity is associated with an increased risk of premature death and cardiovascular disease in later life. Pregnancy is a key time when women receive input from health care professionals and are motivated to improve their health. This period could represent a window of opportunity for interventions to reduce obesity.

Objective To determine whether a combined therapy with isosorbide mononitrate (40mg) and misoprostol (400μg) for pre-operative cervical ripening in the first trimester would result in improved clinical effectiveness, and fewer side effects compared with each agent used alone. Design Randomised controlled trial. Setting Glasgow Royal Infirmary. Population Sixty-six primigravid women scheduled for suction termination of pregnancy. Methods Women were randomly assigned to receive before surgery, per vaginam, isosorbide mononitrate 40 mg (n=22), misoprostol 400 μg (n=22) or both agents together [isosorbide mononitrate 40 mg and misoprostol 400 μg] (n=22). Main outcome measures 1. To assess the cumulative force required to dilate the cervix to 8 mm; 2. the onset of new symptoms before termination of pregnancy. Results The cervical resistance following combination therapy with isosorbide mononitrate and misoprostol was not significantly different than following misoprostol alone [24.5N vs 18.5N; median difference (95% CI) 19N (-22 to 49)]. Pre-treatment with misoprostol used alone resulted in a lower cervical resistance than isosorbide mononitrate alone (18.5Nvs 39N, P=0.04, Mann-Whitney U test). There was no difference in the number of women remaining asymptomatic following either isosorbide mononitrate or misoprostol or combination therapy [14/22 (64%) vs 11/21 (52%) vs 11/22 (50%), Fisher's exact test]. Conclusions We have not shown any advantage of combining misoprostol with the nitric oxide donor isosorbide mononitrate compared with misoprostol alone for pre-operative cervical ripening in the first trimester.

The authors present the first case report of a patient with morbid obesity who developed fat necrosis of the abdominal pannus following caesarean section. The patient was a 40-year-old primigravida with a body mass index of 44 kg/m2. After a relatively uncomplicated antenatal course, she underwent an emergency caesarean section for delay in first stage of labour at 2 cm dilation after induction of labour at 37 weeks gestation for non-proteinuric hypertension. Her immediate post natal period was uncomplicated and she was discharged on day 7 following removal of staples and deep tension sutures. She represented 3 weeks later with a 4 cm necrotic ulcer, 10 cm superior and distinctly separate to the caesarean section wound which was well healed. An ultrasound scan demonstrated a cavity 6×6×20 cm within the pannus. The patient was systemically well and swabs were negative. She was managed conservatively with twice weekly review by a multidisciplinary team including surgeons and obstetricians. However, by 6 weeks postnatal the necrotic area had enlarged to 10×8 cm, had started to leak copious amounts of offensive fatty exudate and there was new onset of cellulitis. The pannus was therefore debrided twice leaving a 20×5×8 cm defect. At operation, there was extensive fat necrosis of the abdominal pannus. Vacuum assisted closure therapy was used for 4 weeks. The wound was completely healed by 5 months postpartum. Dependant oedema and retraction of the pannus at operation may increase the risk of fat necrosis in morbidly obese women undergoing caesarean section.

Two mitochondrial genes, the protein-coding cytochrome c oxidase subunit II (COII) gene and a portion of the 12S rRNA gene, were used for phylogenetic investigation of the mammalian order Perissodactyla. The primary objective of the study was to utilize the extensive fossil record of perissodactyls for calibrating molecular clocks and comparing estimates of divergence times using both genes and two fossil calibration points. Secondary objectives included clarification of previously unresolved relationships within Tapiridae and comparison of the results of separate and combined analyses of two genes. Analyses included several perissodactyl lineages representing all three families (Tapiridae, Equidae, and Rhinocerotidae), most extant genera, all four species of tapirs, two to four species of rhinoceros, and two species of Equus. The application of a relatively recent fossil calibration point and a relatively ancient calibration point produced greatly different estimates of evolutionary rates and divergence times for both genes, even though a relative rates test did not find significant rate differences among taxa. A likelihood-ratio test, however, rejected a molecular clock for both genes. Neither calibration point produced estimates of divergence times consistent with paleontological evidence over a range of perissodactyl radiations. The combined analysis of both genes produces a well-resolved phylogeny with Perissodactyla that conforms to traditional views of interfamilial relationships and supports monophyly of neotropical tapirs. Combining the data sets increases support for most nodes but decreases the support for a neotropical tapir clade because the COII and 12S rRNA data sets are in conflict for tapir relationships.

Objective To determine whether recurrent miscarriage is associated with reduced selenium status. Design Case–control study. Setting Department of Obstetrics and Gynaecology, Glasgow Royal Infirmary and Glasgow Royal Maternity Hospital. Population Twenty nonpregnant women with a history of unexplained recurrent miscarriage, and 47 nonpregnant parous women with a history of at least one successful pregnancy and no more than one miscarriage. Methods A 7 mL blood sample from each woman was collected into lithium heparin ‘vacutainer’ tubes. Samples were centrifuged at 3000 g for 15 minutes, and plasma was extracted and stored at −20°C. Selenium concentrations were measured using a fluorescence spectrophotometer. The selenium concentrations in the two groups were compared and the differences examined using the Student's t test. Main outcome measures Plasma selenium concentration (μg/L). Results The mean selenium concentration for women with a history of unexplained recurrent miscarriage was 67.7 μg/L (SD 16.4). The selenium level for the women with no history of recurrent miscarriage was 70.3 μg/L (SD 12.7). There was no difference in selenium concentrations between the two groups (P= 0.53). Conclusions In this study there is no association between unexplained recurrent miscarriage and reduced selenium status, implying that reduced selenium status is not a factor in the pathogenesis of recurrent miscarriage. We can find no rationale for a trial of selenium therapy in women with a history of recurrent miscarriage.

Nitric oxide (NO) donors are capable of ripening the human cervix during pregnancy. The purpose of this study was to examine how NO donors may be involved in this process. Cervical biopsies were obtained from pregnant women randomized to receive isosorbide mononitrate (n = 10) or no treatment (n = 10) prior to suction termination. Enzyme-linked immunosorbent assays (ELISA) were performed on culture supernatant for interleukin (IL)-1, IL-6, IL-8, IL-10, IL-15, tumour necrosis factor-alpha, monocyte chemoattractant protein-1 and prostaglandin metabolites. Immunohistochemistry was performed to localize these cytokines, cyclooxygenase (COX)-1, COX-2 and prostaglandin dehydrogenase in cervical tissue and reverse transcription-polymerase chain reaction (RT-PCR) to identify COX-1 and COX-2 expression. Biopsies treated with the NO donor isosorbide mononitrate (IMN) produced significantly greater amounts of prostaglandin F(2alpha) in culture and lower amounts of thromboxane B(2) than controls (572.8 versus 34.9 pg/ml, P < 0.05; 53.3 pg/ml versus 530.9 pg/ml, P < 0.01 respectively). The release of other prostaglandins and of cytokines was not affected by treatment with NO. Inflammatory mediators were localized to cervical tissue and COX-1 and COX-2 expression was confirmed by RT-PCR. In conclusion, the mechanism of NO donor-induced cervical ripening during pregnancy may be mediated in part via increased prostaglandin F(2alpha) synthesis.

We have investigated the presence of matrix metallo-proteinases (MMP)-2 and -9 and their tissue inhibitors (TIMP) in the human uterine cervix. We postulate that during the process of cervical ripening, there is an increase in the activity of MMP in order to facilitate cervical connective tissue change. We have previously demonstrated that nitric oxide (NO) donors induce cervical ripening in vivo. A secondary hypothesis is that NO donors regulate MMP activity within the human uterine cervix. Cervical tissue biopsies were obtained from both pregnant and non-pregnant subjects. Cervical fibroblasts were cultured from the non-pregnant tissue. MMP-2 was present in conditioned media from pregnant and non-pregnant cervical explants and non-pregnant cervical fibroblasts. MMP-9 secretion was only detected in explants from non-pregnant women. TIMP-1, -2 and -4 were released by all cervical explants and fibroblast preparations. Pregnant women, in the first trimester, were treated with an NO donor (isosorbide mononitrate) in vivo, Cervical explants and fibroblasts from non-pregnant women were treated with the NO donor spermine nonoate in vitro. Treatment with an NO donor either in vivo or in vitro had no effect on the secretion of the MMP or TIMP studied. Further studies evaluating the mechanisms involved in cervical ripening are required.

Nitric oxide (NO), derived from L-arginine by the action of nitric oxide synthase (NOS), is a mediator of many diverse biological activities, including vasodilation, neurotransmission and inhibition of platelet adhesion. A role for NO in the maintenance of rat and rabbit pregnancy is supported by a variety of studies. A recent study in women demonstrated that myometrial inducible NOS (iNOS) expression was greater in the early third trimester than either the late third trimester or in the non-pregnant condition, suggesting that increased iNOS expression is involved in the maintenance of human pregnancy. Constitutive NOS (cNOS) expression was not determined. The aim of this study was to compare constitutive NOS (both eNOS and bNOS) expression in the human non-pregnant uterus, preterm pregnant uterus (25-34 weeks gestation) and term pregnant uterus (>37 weeks gestation) using immunohistochemistry and Western blotting. Preterm pregnant samples were taken from women with a variety of pathologies necessitating early delivery. We found that eNOS and bNOS protein concentrations were greater in the preterm pregnant myometrium than non-pregnant myometrium. eNOS, but not bNOS, protein concentration was lower in myometrial samples obtained at term compared with those obtained preterm. We conclude that the constitutive isoforms of NOS are also up-regulated in human pregnancy and may play a role in the maintenance of myometrial quiescence.

The purpose of this study was to localize intercellular adhesion molecule (ICAM)-1 and ICAM-2 in human endometrium and myometrium throughout the menstrual cycle, and to determine whether the expression of these molecules is regulated by interferon (IFN)-gamma. ICAM-1 and ICAM-2 distribution was examined in endometrial biopsies by immunocytochemistry, and Northern blotting was used to quantify ICAM-1 and ICAM-2 mRNA expression in isolated endometrial glands. Stromal fibroblast cultures were exposed to IFN-gamma and the effect on expression of ICAM-1 and ICAM-2 was determined by immunocytochemistry and Northern blotting. ICAM-1 was localized in vivo to the apical surface of the glandular epithelium, the vascular endothelium and endometrial stromal cells throughout the menstrual cycle. Stromal expression of ICAM-1 was up-regulated in menstrual specimens. Northern blotting confirmed the presence of ICAM-1 mRNA in isolated endometrial glands. The expression of ICAM-1 antigen and message was increased in stromal cell culture after incubation with IFN-gamma in a time-dependent manner, suggesting that this cytokine stimulates the expression of ICAM-1 in the endometrial stroma. ICAM-2 antigen expression was restricted to the vascular endothelium. ICAM-2 mRNA was absent in endometrial glands. The widespread distribution of ICAM-1 in human endometrium suggests that this molecule is involved in the process of menstruation, the functioning of glands, blood vessels and stroma, and in regulating leukocyte trafficking into the tissue. ICAM-2 is restricted to the vascular endothelium where it might modulate leukocyte invasion of the stroma and myometrial connective tissue.

To determine lower genital tract carriage rates of C. trachomatis, N. gonorrhoeae and bacterial vaginosis among women seeking termination of pregnancy. To compare two clinical management strategies for minimising the risks of infective morbidity after induced abortion.Prevalence of infections was assessed by screening women undergoing abortion. Clinical management strategies were compared by a randomised trial.The gynaecology departments of four hospitals in Scotland.1672 women undergoing induced abortion.Women randomised to prophylaxis received metronidazole 1 g rectally before abortion plus doxycycline 100 mg twice daily for seven days. Women randomised to screen-and-treat received appropriate antibiotics only if screening proved positive for one or more infection.Prevalences of infections; morbidity in the eight weeks following abortion as assessed by reported symptoms, general practitioner consultation and prescription rates and hospital re-attendances; costs to the NHS of alternative managements.Prevalence rates: C. trachomatis 5.6%; N gonorrhoeae 0.19%; bacterial vaginosis 17.5%. Overall, women allocated to receive prophylaxis had lower rates of measures of short term infective morbidity than those allocated to screen-and-treat. These differences only reached statistical significance for women who were reported negative on screening. The direct costs to the NHS of prophylaxis and screen-and-treat were calculated to be 8.17 and 18.34 per woman, respectively.Prevalences of lower genital tract infections which have been implicated in increased rates of infective morbidity after abortion are similar to those reported elsewhere. Universal antibiotic prophylaxis is at least as effective as a policy of screen-and-treat in minimising the risk of short term infective morbidity and is far more cost efficient.The presence of infection in the lower genital tract at the time of induced abortion has been associated with an increased risk of postabortion pelvic inflammatory disease (PID). The present study investigated the prevalences of Neisseria gonorrhoeae, Chlamydia trachomatis, and bacterial vaginosis among 1672 women undergoing induced abortion at four Scottish hospitals in 1995-96. It further compared the effectiveness of two clinical management strategies for minimizing the risk of postabortion infection. Women were randomly assigned to receive either 1 g of metronidazole rectally before abortion and 100 mg/day of doxycycline for 7 days (n = 826) or treatment only if screening was positive for infection (n = 846). Preabortion lower genital tract screening indicated 3 women (0.2%) were positive for N. gonorrhoeae, 91 (5.6%) for C. trachomatis, and 282 (17.5%) for bacterial vaginosis. A review of the rates of general practitioner consultations, antibiotic prescriptions, and hospital readmissions in the 8 weeks postabortion showed that symptoms were minor and similar in duration and intensity among women in both treatment groups. The postabortion PID/endometriosis rate was 4.6% among women in the prophylaxis group and 6.8% in the screen-and-treat group. Women in these two groups who were initially positive for 1 or more infection had significantly higher rates of postabortion PID/endometriosis (7.7% and 7.4%, respectively) than those who were initially negative (3.1% and 5.7%, respectively). Antibiotics had to be prescribed postabortion to 13.1% of women initially positive for 1 or more infection compared with 7.8% of those initially negative. The cost of universal prophylaxis (8.17 pounds) was less than half that of screening with treatment and follow up of positive cases.

Superoxide, an agent which attenuates the half-life of nitric oxide, is metabolized and synthesized by superoxide dismutase (SOD) and xanthine oxidase, respectively. Over the last few years much work has focused on the role of nitric oxide in human parturition. The aim of this study was to determine whether the onset of human parturition is associated with a change in the expression of copper/zinc superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (Mn SOD) or xanthine oxidase within the uterus. Samples of myometrium, placenta, decidua and fetal membranes were obtained from women before and after the onset of labour at term. Immunocytochemistry was used to localize Cu/Zn SOD, Mn SOD and xanthine oxidase and measure SOD enzyme activity. Cu/Zn and Mn SOD-like immunoreactivity was detected in syncytiotrophoblast cells, villous stromal cells and endothelial cells of blood vessels in the placenta. In the myometrium Cu/Zn and Mn SOD were localized to myocytes and endothelial cells and to some vascular smooth muscle cells. In the fetal membranes we observed staining for Cu/Zn SOD and Mn SOD in the amnion, chorion, extravillous trophoblast and decidua. There was no difference in SOD enzyme activity or staining intensity for SOD between different cell types before and during labour. Xanthine oxidase immunoreactivity was identified in each of the tissues examined and again there was no difference in immunostaining in tissues obtained from women delivered before or after the onset of labour. These results show that the pregnant uterus is capable of both synthesizing and degrading superoxide and suggest that superoxide dismutase and xanthine oxidase may play a role in the maintenance of uterine quiescence during pregnancy, but not in the initiation of parturition.

Objective To determine whether nitric oxide donors can induce cervical ripening before surgical termination of pregnancy in the first trimester. Design Prospective, randomised controlled trial. Setting Department of Obstetrics and Gynaecology, Royal Infirmary, Glasgow. Participants Forty-eight primigravid women undergoing surgical termination of pregnancy before 12 weeks of gestation. Methods The women were randomised to receive per vaginam before surgery either the nitric oxide donor isosorbide mononitrate, the nitric oxide donor glyceryl trinitrate, the prostaglandin analogue gemeprost, or no treatment. Main outcome measures The cumulative force required to dilate the cervix to 8 mm was measured objectively and the cervical diameter before surgical dilatation was recorded. Results Following isosorbide mononitrate or gemeprost, a lower cumulative force was required to dilate the cervix to 8 mm and a higher cervical diameter before dilatation was recorded. Pretreatment with glyceryl trinitrate reduced the cumulative force required to dilate the cervix but had no effect on cervical diameter. Conclusions Like the prostaglandin analogue gemeprost, the nitric oxide donors isosorbide mononitrate and glyceryl trinitrate can effect cervical ripening. Nitric oxide donors may provide an alternative to prostaglandins for cervical ripening before surgical procedures in the first trimester.

The purpose of this study was to determine the relaxant effects in vitro of two nitric oxide donors, glyceryl trinitrate and sodium nitroprusside, which are currently available for use in vivo, on contractions of non-labouring myometrium from pregnant women. Since nitric oxide also mediates relaxation by increasing the concentration of cGMP, sensitivity to 8-bromo-cGMP (a cGMP analogue) was also determined. The effects of the K(+)-channel opener lemakalim and of the Ca(2+)-channel blocker nifedipine were studied for comparison. After the addition of glyceryl trinitrate (0.1-100 mumol l-1), sodium nitroprusside (0.1-100 mumol l-1) or 8-bromo-cGMP (0.001-3 mmol l-1), the spontaneous rhythmic contractility of myometrial strips was inhibited in a concentration-dependent manner: the maximum inhibition produced by the highest tested concentration of each drug was 40 +/- 7%, 53 +/- 8% and 39 +/- 8% of the original degree of contraction, respectively. Myometrial contractions were completely abolished by lemakalim and by nifedipine and verapamil at concentrations of > or = 10(-5) mol l-1. The nitric oxide donors, glyceryl trinitrate and sodium nitroprusside, attenuate myometrial contractions and are therefore useful as tocolytic agents. However, at equimolar concentrations in vitro, the ability of glyceryl trinitrate and sodium nitroprusside to attenuate myometrial contractions is less than that of lemakalin, nifedipine and verapamil. Controlled trials are required to determine the side-effects and clinical efficacy of each of these agents in vivo.

Introduction G-protein coupled receptors (GPCRs) are critical mediators of platelet responses to stimulatory and inhibitory agonists. In rare families with mild bleeding, it is recognised that heterozygous loss of function variations in platelet GPCR genes may diminish platelet agonist responses. However, the population prevalence of loss of function variations in these genes is unknown. We have utilised population databases and next generation sequencing from patients with inherited platelet function disorders (IPFD) to describe the extent of genetic variation in the major platelet GPCRs. We have also used predictive computation and a new consensus structure of GPCRs (Venkatakrishnan AJ et al.Nature 2013; 494) to estimate which variations confer loss of function. Methods We interrogated the ESP and 1000 genomes population datasets for single nucleotide (SNV) and insertion-deletion (indel) variations in the genes encoding 6 stimulatory (ADRA2A, F2R, F2RL3, P2RY1, P2RY12, TBXA2R) and 2 inhibitory (PTGER4, PTGIR) platelet GPCRs. Coding and splice region variations within the relevant Refseq transcripts were functionally annotated using the Polyphen-2, SIFT and FATHMM algorithms. Missense variations within GPCR transmembrane (TM) domains, were annotated manually by expressing the substitutions in Ballesteros-Weinstein nomenclature before comparison with the consensus GPCR structure. Missense variations in the N- and C-terminal regions (NR and CR) and the intra- and extra- cellular loops (ICL and ECL) were annotated by identifying the position of the substituted residue relative to experimentally confirmed or putative functional motifs. An identical analysis was performed using exome data from 31 unrelated patients with IPFD recruited through the UK GAPP study with clinical bleeding and abnormal platelet function by light transmission aggregation. Results In 7745 individuals from the ESP and 1000 genomes cohorts, we identified 332 SNV in the target regions of the 8 GPCR genes (40.5 variations/kb) comprising 183 non-synonymous and 148 synonymous coding variants and 4 variations within intronic splice regions. There were no indel variations. Functional annotation of the non-synonymous SNVs identified 41 that potentially conferred loss of function, distributed in all the target GPCRs but with low population frequency (minor allele frequency range 1-0.008%). Five SNVs affected the NT, including Gly48Asp and Arg47His substitutions at the PAR4 receptor thrombin/trypsin cleavage site. There were 12 SNVs affecting the TM domains, of which 4 were predicted to disrupt GPCR folding, including a TPα receptor Pro305Leu substitution within the structural N/DPXXY motif and the P2Y12 receptor Met108Leu and Thr283Ile substitutions predicted to disrupt non-covalent TM network contacts. There were 14 SNVs affecting the ICL including the P2Y12 receptor Asp121Asn substitution in the E/DRY motif and prostacyclin (IP1) receptor Arg212Cys and Arg215Cys substitutions predicted to disrupt Gs coupling. Ten functional SNVs affected the CT. In 31 IPFD patients with complex laboratory phenotypes that could not be explained by loss of a single GPCR, there were 8 non-synonymous SNVs, of which 5 were predicted to confer loss of function (table). Discussion In unselected populations, heterozygous loss of function GPCR gene variations which potentially affect platelet agonist responses are individually rare, but collectively numerous. Loss of function GPCR variations were also present in patients with underlying IPFD. These data illustrate that variations in platelet regulatory genes may act as modifiers of laboratory phenotype in patients with underlying IPFD and that the net phenotype may be the product of multiple gene defects. Disclosures: No relevant conflicts of interest to declare.

Maternal perception of fetal movements is the oldest and most commonly used method to evaluate fetal wellbeing. The investigation and management of reduced fetal movements (RFM) is complicated by a wide variation in the amount perceived by individual mothers and the paucity of good evidence to guide clinicians. This survey was designed in line with the RCOG Green-top Guideline on Reduced Fetal Movements (February 2011) using www.surveymonkey.com and was distributed to all trainee and consultant obstetricians and all midwifery staff across Scotland. 200 responses were collected; 68% from midwives and 32% from obstetric trainees or consultants. 63% of responders were aware of the RCOG guideline on RFM; of these, 79% had read this guideline. Despite this, only 69% work in a unit which has a policy detailing investigations and management of women presenting with RFM. 80% of responders accepted “maternal perception of decreased fetal movements” as a definition of RFM and an indication to seek advice. Over 90% of responders routinely perform CTG (if greater than 28 weeks), blood pressure and urinalysis on women presenting with RFM. Less than 5% would routinely refer women with RFM for ultrasound examination without additional risk factors and only 67% of responders have access to this within 24 hrs or during the next working day. Surprisingly, 23% would never offer induction for RFM. The results reveal the huge variation across Scotland when investigating and managing women presenting with RFM, highlighting the importance of further research into the issue and the development of nationally agreed policy.

Commentary on: Dodd J, Crowther C, Haslam R, et al., for the Twins Timing of Birth Trial Group. Elective birth at 37 weeks of gestation versus standard care for women with an uncomplicated twin pregnancy at term: the Twins Timing of Birth Randomised Trial. BJOG 2012; 119: 964– 74.[OpenUrl][1][CrossRef][2][PubMed][3] In singleton pregnancies, offering elective delivery at or beyond term (40 weeks gestation) reduces perinatal mortality.1 ,2 Epidemiological data suggest that in twin pregnancies ‘term’ may be earlier than in singletons. Morbidity and mortality in twin pregnancies is the lowest in association with delivery at 36–38 weeks gestation, leading the National Institute for Health and Clinical Excellence (NICE) to endorse elective delivery around 37 weeks for dichorionic twins and 36 weeks for monochorionic twins.3 Data from randomised trials evaluating such a policy is lacking. Dodd and colleagues report the results of a randomised controlled trial of elective delivery … [1]: {openurl}?query=rft.jtitle%253DBJOG%2B%253A%2B%2Ban%2Binternational%2Bjournal%2Bof%2Bobstetrics%2Band%2Bgynaecology%26rft.stitle%253DBJOG%26rft.aulast%253DDodd%26rft.auinit1%253DJ.%26rft.volume%253D119%26rft.issue%253D8%26rft.spage%253D964%26rft.epage%253D973%26rft.atitle%253DElective%2Bbirth%2Bat%2B37%2Bweeks%2Bof%2Bgestation%2Bversus%2Bstandard%2Bcare%2Bfor%2Bwomen%2Bwith%2Ban%2Buncomplicated%2Btwin%2Bpregnancy%2Bat%2Bterm%253A%2Bthe%2BTwins%2BTiming%2Bof%2BBirth%2BRandomised%2BTrial.%26rft_id%253Dinfo%253Adoi%252F10.1111%252Fj.1471-0528.2012.03356.x%26rft_id%253Dinfo%253Apmid%252F22691051%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1111/j.1471-0528.2012.03356.x&link_type=DOI [3]: /lookup/external-ref?access_num=22691051&link_type=MED&atom=%2Febmed%2F18%2F3%2Fe21.atom

Rationale/statement of the problem : One in five UK women is obese at antenatal booking. Maternal obesity increases risk of offspring obesity, behavioural and metabolic disorders. Animal studies suggest male offspring are more vulnerable to these effects than females. We hypothesised that this is mediated by altered action of maternal glucocorticoids, key regulators of development and stimulators of appetite and weight gain. Methods : Serum cortisol levels were measured at 16, 28 and 36 weeks gestation in n=156 class III obese (BMI > 40 kg/m2) and n=87 lean (BMI 4000 g) offspring (p