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Introduction Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels 1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000–10 000 IU/L Methods and analysis We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000–10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m2) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels

Preterm birth is the single biggest cause of significant neonatal morbidity and mortality, and the incidence is rising. Development of new therapies to treat and prevent preterm labour is seriously hampered by incomplete understanding of the molecular mechanisms that initiate labour at term and preterm. Computational modelling provides a new opportunity to improve this understanding. It is a useful tool in (i) identifying gaps in knowledge and informing future research, and (ii) providing the basis for an in silico model of parturition in which novel drugs to prevent or treat preterm labour can be “tested”. Despite their merits, computational models are rarely used to study the molecular events initiating labour. Here, we present the first attempt to generate a dynamic kinetic model that has relevance to the molecular mechanisms of preterm labour. Using published data, we model an important candidate signalling pathway in infection-induced preterm labour: that of lipopolysaccharide (LPS) -induced activation of Nuclear Factor kappa B. This is the first model of this pathway to explicitly include molecular interactions upstream of Nuclear Factor kappa B activation. We produced a formalised graphical depiction of the pathway and built a kinetic model based on ordinary differential equations. The kinetic model accurately reproduced published in vitro time course plots of Lipopolysaccharide-induced Nuclear Factor kappa B activation in mouse embryo fibroblasts. In this preliminary work we have provided proof of concept that it is possible to build computational models of signalling pathways that are relevant to the regulation of labour, and suggest that models that are validated with wet-lab experiments have the potential to greatly benefit the field.

Objective To investigate the impact of maternal body mass index (BMI, kg/m2) on clinical complications, inpatient admissions, and additional short-term costs to the National Health Service (NHS) in Scotland. Design Retrospective cohort study using an unselected population database. Setting Obstetric units in Scotland, 2003–2010. Population A total of 124 280 singleton deliveries in 109 592 women with a maternal BMI recorded prior to 16 weeks of gestation. Methods Population-based retrospective cohort study of singleton deliveries, with multivariable analysis used to assess short-term morbidity and health service costs. Main outcome measures Maternal and offspring outcomes, number and duration of hospital admissions, and healthcare costs. Results Using multivariable analysis, in comparison with women of normal weight, women who were overweight, obese, or severely obese had an increased risk of essential hypertension [1.87 (1.18–2.96), 11.90 (7.18–19.72), and 36.10 (18.33–71.10)], pregnancy-induced hypertension [1.76 (1.60–1.95), 2.98 (2.65–3.36), and 4.48 (3.57–5.63)], gestational diabetes [3.39 (2.30–4.99), 11.90 (7.54–18.79), and 67.40 (37.84–120.03)], emergency caesarean section [1.94 (1.71–2.21), 3.40 (2.91–3.96), and 14.34 (9.38–21.94)], and elective caesarean section [2.06 (1.84–2.30), 4.61 (4.06–5.24), and 17.92 (13.20–24.34)]. Compared with women of normal weight, women who were underweight, overweight, obese, or severely obese were associated with an 8, 16, 45, and 88% increase in the number of admissions, respectively, and women who were overweight, obese, or severely obese were associated with a 4, 9, and 12% increase in the duration of stay (all P

To investigate the effect of omega-3 PUFAs, eicosapentanoic acid (EPA) and docosohexanoic acid (DHA) on inflammatory cytokine production in the amnion.Amnion explants were obtained at elective caesarean sections and cultured in vitro with EPA and DHA. IL-8 and IL-6 secretion was determined by ELISA, the role of PPARγ was investigated using specific agonists and antagonists and activity of MMP assessed by gelatin zymography.A combination of EPA and DHA significantly reduced the concentration of IL-8 and IL-6 released into the supernatant compared to untreated controls (p0.001). Stimulation of PPARγ with troglitazone reduced IL-8 production, and the PPARγ antagonist GW9662 partially reversed this effect. The activity of MMP-9 was also significantly reduced by treatment with EPA and DHA in combination compared to untreated control (p0.05).The omega-3 PUFAs EPA and DHA decrease the inflammatory response of the amnion, and this may be partially mediated through PPARγ.

Background: There is evidence that induction of labour (IOL) around term reduces perinatal mortality and caesarean delivery rates when compared to expectant management of pregnancy (allowing the pregnancy to continue to await spontaneous labour or definitive indication for delivery). However, it is not clear whether IOL in women with a previous caesarean section confers the same benefits. The aim of this study was to describe outcomes of IOL at 39–41 weeks in women with one previous caesarean delivery and to compare outcomes of IOL or planned caesarean delivery to those of expectant management.\ud \ud Methods and Findings: We performed a population-based retrospective cohort study of singleton births greater than 39 weeks gestation, in women with one previous caesarean delivery, in Scotland, UK 1981–2007 (n = 46,176). Outcomes included mode of delivery, perinatal mortality, neonatal unit admission, postpartum hemorrhage and uterine rupture. 40.1% (2,969/7,401) of women who underwent IOL 39–41 weeks were ultimately delivered by caesarean. When compared to expectant management IOL was associated with lower odds of caesarean delivery (adjusted odds ratio [AOR] after IOL at 39 weeks of 0.81 [95% CI 0.71–0.91]). There was no significant effect on the odds of perinatal mortality but greater odds of neonatal unit admission (AOR after IOL at 39 weeks of 1.29 [95% CI 1.08–1.55]). In contrast, when compared with expectant management, elective repeat caesarean delivery was associated with lower perinatal mortality (AOR after planned caesarean at 39 weeks of 0.23 [95% CI 0.07–0.75]) and, depending on gestation, the same or lower neonatal unit admission (AOR after planned caesarean at 39 weeks of 0.98 [0.90–1.07] at 40 weeks of 1.08 [0.94–1.23] and at 41 weeks of 0.77 [0.60–1.00]).\ud \ud Conclusions: A more liberal policy of IOL in women with previous caesarean delivery may reduce repeat caesarean delivery, but increases the risks of neonatal complications.

The four extant members of the family Tapiridae have a disjunct, relictual distribution, with three species being Neotropical (Tapirus bairdii, T. terrestris, andT. pinchaque) and one found in Southeast Asia (T. indicus). Little recent work on tapir systematics have appeared, and no molecular studies of this group have been published. A phylogenetic analysis was undertaken using sequences of the mitochondrial cytochromec oxidase subunit II gene (COII) from representatives of the four species of tapirs, as well as a representative outgroup,Equus caballus. Analyses of the COII sequences indicate a close relationship between the two South American species of tapirs,T. terrestris andT. pinchaque, and estimates of divergence dates using rates of COII evolution are compatible with migration of a single tapir lineage into South America following the emergence of the isthmus of Panama, about 3 million years bp. Various methods of analysis, including maximum parsimony, maximum likelihood, and neighbor-joining, provided poorer resolution of other tapir relationship. The COII data suggest that three distinct tapir mitochondrial lineages, a South American (represented byT. terrestris andT. pinchaque), a Central American (represented byT. bairdii), and an Asian (represented byT. indicus) diverged relatively rapidly, 20–30 million years bp. Another goal of this study was to calibrate the rate of COII evolution in a eutherian mammal group which has a good fossil record, such as perissodactyls, to estimate accurately the rate of COII evolution in a nonprimate mammalian group. The rate of COII evolution in equids and tapirs has been relatively constant and, using corrected distances, calibrated to be approximately 0.22% lineage/million years. This rate is three-to fourfold lower than that of hominoid primates.

In 1987, the gas nitric oxide (NO) was shown to possess the physical and pharmacological properties of Furchgott’s endothelium-derived relaxing factor (EDRF). It is now recognized that this ubiquitous molecule plays a crucial role in a host of biological systems (Furchgott and Zawadzki, 1980; Palmer et al., 1987; Moncada and Higgs, 1993; Anggard, 1994). Nitric oxide is a smooth muscle relaxant in the vascular system, lungs and the gastrointestinal tract. It is a neurotransmitter in the brain and peripheral nervous system, and is involved in activities as diverse as memory and insulin release from islet cells. Furthermore, NO is produced by macrophages and other cells of the immune system in large quantities as part of the defence mechanism against foreign organisms and malignant cells. Given the pervasive nature of NO, it is not surprising that it is produced by and intimately involved in the functions of the female reproductive tract. For example, it may play a role in regulating blood loss during, and preventing the development of intrauterine adhesions following, menstruation. In pregnancy, NO may be involved in the regulation of blood flow through the fetoplacental circulation and it may be pivotal for the maintenance of myometrial quiescence. This review aims to examine the sites of production and the function of NO in the human uterus. In each situation in which a role for NO has been proposed in women, results will be supported by studies using animal models.

Nitric oxide (NO) is a potent smooth muscle relaxant in blood vessels, the gastrointestinal tract and the respiratory system. Recent evidence has shown that NO has a relaxant (tocolytic) effect on myometrium. NO is produced within the female genital tract during pregnancy, and a reduction in NO synthesis may be involved in the initiation of parturition. Furthermore, the administration of NO donors may be useful in inhibiting uterine contractions in situations where such activity is unwanted, e.g., in preterm labour. NO is also produced in the myometrium in the nonpregnant state, and has potential roles in the facilitation of implantation and the prevention of dysmenorrhoea. This article aims to examine the evidence suggesting that NO has a physiological role in the maintenance of pregnancy and potential pharmacological use in the treatment of preterm labour.

Women with polycystic ovary syndrome (PCOS) are increasingly being treated with metformin as an insulin sensitizing agent to reduce symptoms of hyperandrogenism and promote fertility. Indications such as hirsutism and cycle regulation require long term treatment. The drug is also being used through pregnancy. It is not licensed for any indication specific to PCOS, which means that much of this prescribing is taking place in an environment short of reliable information concerning safety. We describe the failure of recruitment to a study undertaken to explore the effects of metformin treatment discontinuation in women with PCOS, to provide both clinical and aetiological information. The study failed because the patients did not wish to stop treatment, and it illustrates the problems facing doctors working in this area. To achieve a safer prescribing environment, we recommend that action be taken by the manufacturer of metformin to work with regulatory agencies on a European base to extend prescribing indications for metformin to women with PCOS.

The aim of this study was to investigate the presence of nitric oxide synthase (NOS) in human uterus. Tissues were obtained at operation from 10 women undergoing hysterectomy for benign disease. In-situ hybridization was used to determine the distribution of mRNA for NOS with a 483 bp digoxigenin-labelled antisense riboprobe. Localization of NOS was detected by (i) immunocytochemistry using a monoclonal antibody raised against bovine constitutive endothelial NOS, and (ii) NADPH diaphorase, which has been suggested to co-localize with brain NOS. Messenger RNA for NOS was detected in endometrium and myometrium from nine of 10 women, predominantly in endometrial glandular epithelium and stroma and myometrial blood vessels. NOS-like immunoreactivity was seen in endometrial stroma and myometrial blood vessels, whereas NADPH diaphorase activity was localized mainly to endometrial glandular epithelium and myometrial blood vessels. These studies suggest that different forms of constitutive NOS are present in human endometrium and myometrium, and that nitric oxide may play a role in the paracrine control of the uterine vascular bed.

Background Cortisol concentrations follow an ultradian rhythm, and these hormone pulses are an important factor governing gene transcription in target tissue. The maternal hypothalamic–pituitary–adrenal axis undergoes dramatic activation during pregnancy with resultant increased circulating cortisol. However, little is known about changes that might occur in pulsatility during this period. We tested our hypothesis that pulse frequency and amplitude are altered during pregnancy. Methods Study visits were at the Edinburgh Royal Infirmary. We recruited eligible women aged 16–45 years with body-mass index of less than 25 kg/m 2 . Exclusion criteria were diabetes, smoking, and use of glucocorticoid therapy or hormonal contraception. Cortisol was measured by ELISA in serum obtained every 10 min for 6 h from five healthy pregnant women (16–24 weeks' gestation [P1] and 30–36 weeks' [P2]), and from three non-pregnant controls [NP]) during the luteal phase of the menstrual cycle. Women gave written, informed consent, and ethics approval was given by the local research ethics committee. Data are given as mean (SD). Findings Fasting serum cortisol, pulse frequency, and pulse amplitude were all significantly higher in pregnancy than in non-pregnancy (all p Interpretation We show that in normal human pregnancy, increased frequency and amplitude of cortisol pulsatility might be a novel mechanism underlying pregnancy complications related to cortisol exposure such as intrauterine growth restriction. Future studies will investigate whether the pulsatility of bioavailable cortisol in peripheral tissue is altered, and characterise the ultradian rhythm of cortisol in high-risk pregnancy groups. Funding Tommy's.

Rationale/statement of the problem : Obesity is associated with increased symptoms of anxiety and depression. We hypothesised that severe obesity in pregnancy would be associated with adverse psychological health, with effects on gestational weight gain (GWG) and baby birthweight (BWT). We aimed to study mood and birth outcomes among participants in a longitudinal study of severe obesity in pregnancy. Methods : In this study, 140 severely obese (body mass index [BMI] (mean (SD)) 44.1 (4.1) kg/m2) and 96 lean (BMI 22.6 (1.6) kg/m2) pregnant women were recruited. Ethical approval and written, informed consent were obtained. Obese women were advised about healthy eating and weight maintenance. Serial weights were recorded and GWG calculated between 16 and 36 weeks’ gestation. Women were asked to complete validated questionnaires to assess mood, including ‘satisfaction with life’, Hospital Anxiety and Depression Scale (HADS) and Spielberger State and Trait Anxiety in early (12–20 weeks’ gestation) and late pregnancy (28–32 weeks’ gestation). Term BWT (>37 weeks’ gestation) was recorded (n=234). Results : Obese women were significantly less satisfied with life than lean women and had higher HADS depression and anxiety scores, and state and trait anxiety scores at both time points (all p

Background Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location. Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the “progesterone” group having a lower incidence of preterm birth. Methods/Design The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22 – 34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites. Discussion OPPTIMUM will provide further evidence on the effectiveness of vaginal progesterone for prevention of preterm birth and improvement of neonatal outcomes in selected groups of women with singleton pregnancy at high risk of preterm birth. Additionally it will determine whether any reduction in the incidence of preterm birth is accompanied by improved childhood outcome. Trial registration ISRCTN14568373

Background Immediate delivery of the preterm fetus with suspected compromise may decrease the risk of damage due to intrauterine hypoxia. However, it may also increase the risks of prematurity. Objectives To assess the effects of immediate versus deferred delivery of preterm babies with suspected fetal compromise on neonatal, maternal and long-term outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2016) and reference lists of retrieved studies. Selection criteria Randomised trials comparing a policy of immediate delivery with deferred delivery or expectant management in preterm fetuses with suspected in utero compromise. Quasi-randomised trials and trials employing a cluster-randomised design were eligible for inclusion but none were identified. Data collection and analysis Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Main results We included one trial of 548 women (588 babies) in the review. Women with pregnancies between 24 and 36 weeks' gestation took part. The study took place in 13 European countries, between 1993 and 2001. The difference in the median randomisation to delivery interval between immediate delivery and deferred delivery was four days (median: 0.9 (inter-quartile range (IQR) 0.4 to 1.3) days for immediate delivery, median: 4.9 (IQR 2.0 to 10.8) days in the delay group). There was no clear difference in the primary outcomes of extended perinatal mortality (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.67 to 2.04, one trial, 587 babies, moderate-quality evidence) or the composite outcome of death or disability at or after two years of age (RR 1.22, 95% CI 0.85 to 1.75, one trial, 573 babies, moderate-quality evidence) with immediate delivery compared to deferred delivery. The results for these outcomes are consistent with both appreciable benefit and harm. More babies in the immediate delivery group were ventilated for more than 24 hours (RR 1.54, 95% CI 1.20 to 1.97, one trial, 576 babies). There were no differences between the immediate delivery and deferred delivery groups in any other infant mortality outcome (stillbirth, neonatal mortality, postneonatal mortality > 28 days to discharge), individual neonatal morbidity or markers of neonatal morbidity (cord pH less than 7.00, Apgar less than seven at five minutes, convulsions, interventricular haemorrhage or germinal matrix haemorrhage, necrotising enterocolitis and periventricular leucomalacia or ventriculomegaly). Some important outcomes were not reported, in particular infant admission to neonatal intensive care or special care facility, and respiratory distress syndrome. We were not able to calculate composite rates of serious neonatal morbidity, even though individual morbidities were reported, due to the risk of double counting infants with more than one morbidity. More children in the immediate delivery group had cerebral palsy at or after two years of age (RR 5.88, 95% CI 1.33 to 26.02, one trial, 507 children). There were, however, no differences in neurodevelopment impairment at or after two years (RR 1.72, 95% CI 0.86 to 3.41, one trial, 507 children), death at or after two years of age (RR 1.04, 95% CI 0.66 to 1.63, one trial, 573 children), or death or disability in childhood (six to 13 years of age) (RR 0.82, 95% CI 0.48 to 1.40, one trial, 302 children). More women in the immediate delivery group had caesarean delivery than in the deferred delivery group (RR 1.15, 95% CI 1.07 to 1.24, one trial, 547 women, high-quality evidence). Data were not available on any other maternal outcomes. There were several methodological weaknesses in the included study, and the level of evidence for the primary outcomes was graded high for caesarean section and moderate for extended perinatal mortality and death or disability at or after two years. The evidence was downgraded because the CIs for these outcomes were wide, and were consistent with both appreciable benefit and harm. Bias may have been introduced by several factors: blinding was not possible due to the nature of the intervention, data for childhood follow-up were incomplete due to attrition, and no adjustment was made in the analysis for the non-independence of babies from multiple pregnancies (39 out of 548 pregnancies). This study only included cases of suspected fetal compromise where there was uncertainty whether immediate delivery was indicated, thus results must be interpreted with caution. Authors' conclusions Currently there is insufficient evidence on the benefits and harms of immediate delivery compared with deferred delivery in cases of suspected fetal compromise at preterm gestations to make firm recommendations. There is a lack of trials addressing this question, and limitations of the one included trial means that caution must be used in interpreting and generalising the findings. More research is needed to guide clinical practice. Although the included trial is relatively large, it has insufficient power to detect differences in neonatal mortality. It did not report any maternal outcomes other than mode of delivery, or evaluate maternal satisfaction or economic outcomes. The applicability of the findings is limited by several factors: Women with a wide range of obstetric complications and gestational ages were included, and subgroup analysis is currently limited. Advances in Doppler assessment techniques may diagnose severe compromise more accurately and help make decisions about the timing of delivery. The potential benefits of deferring delivery for longer or shorter periods cannot be presumed. Where there is uncertainty whether or not to deliver a preterm fetus with suspected fetal compromise, there seems to be no benefit to immediate delivery. Deferring delivery until test results worsen or increasing gestation favours delivery may improve the outcomes for mother and baby. There is a need for high-quality randomised controlled trials comparing immediate and deferred delivery where there is suspected fetal compromise at preterm gestations to guide clinical practice. Future trials should report all important outcomes, and should be adequately powered to detect differences in maternal and neonatal morbidity and mortality.

BackgroundPlacental insufficiency is a major cause of antepartum stillbirth and fetal growth restriction (FGR). In affected pregnancies, delivery is expedited when the risks of ongoing pregnancy outweigh those of prematurity. Current tests are unable to assess placental function and determine optimal timing for delivery. An accurate, non-invasive test that clearly defines the failing placenta would address a major unmet clinical need. Proton magnetic resonance spectroscopy (1H MRS) can be used to assess the metabolic profile of tissue in-vivo. In FGR pregnancies, a reduction in N-acetylaspartate (NAA)/choline ratio and detection of lactate methyl are emerging as biomarkers of impaired neuronal metabolism and fetal hypoxia, respectively. However, fetal brain hypoxia is a late and sometimes fatal event in placental compromise, limiting clinical utility of brain 1H MRS to prevent stillbirth. We hypothesised that abnormal placental 1H MRS may be an earlier biomarker of intrauterine hypoxia, affording the opportunity to optimise timing of delivery in at-risk fetuses. Methods and Findings We recruited three women with severe placental insufficiency/FGR and three matched controls. Using a 3T MR system and a combination of phased-array coils, a 20×20×40 mm1H MRS voxel was selected along the ‘long-axis’ of the placenta with saturation bands placed around the voxel to prevent contaminant signals. A significant choline peak (choline/lipid ratio 1.35–1.79) was detected in all healthy placentae. In contrast, in pregnancies complicated by FGR, the choline/lipid ratio was ≤0.02 in all placentae, despite preservation of the lipid peak (p Conclusions This novel proof-of-concept study suggests that in severe placentalinsufficiency/FGR, the observed 60-fold reduction in the choline/lipid ratio by 1H MRS may represent an early biomarker of critical placental insufficiency. Further studies will determine performance of this test and the potential role of 1H-MRS in the in-vivo assessment of placental function to inform timing of delivery.

Human parturition is an inflammatory process that can be activated prematurely by pathological stimuli. This study investigated the expression of G protein-coupled receptors GPR43 and GPR41 receptors in human uteroplacental tissues and the role of short-chain fatty acids (SCFA) in modulating inflammatory pathways in fetal membranes. Expression of GPR43 and GPR41 was investigated in uteroplacental tissues collected from women delivering at term or preterm after ethical approval and patient informed consent. The effect of SCFA on expression of inflammatory genes was assessed in amnion explants after culture with a mimetic of infection (lipopolysaccharide, LPS). Sodium propionate effect on LPS-induced neutrophil chemotaxis was evaluated by transwell assay. GPR43 and GPR41 mRNA expression was higher in myometrium and fetal membranes collected from women after the onset of labor. GPR43 protein expression localized to immune cells and vascular endothelium in the myometrium and epithelium of fetal membranes. Treatment with LPS significantly increased mRNA expression of GPR43 and inflammatory genes. Cotreatment with LPS and sodium propionate decreased LPS-induced expression of inflammatory genes including IL-6, IL-8, cyclooxygenase-2, IL-1α, intercellular adhesion molecule-1, and platelet endothelial cell adhesion molecule-1 but not IL-1β or lymphocyte function-associated antigen-1. Sodium propionate reduced LPS-induced neutrophil chemotaxis and protein secretion of the neutrophil chemoattractant IL-8. Finally, fetal membrane expression of GPR43 was significantly higher in women delivering preterm with evidence of infection. GPR43-SCFA interactions may represent novel pathways that regulate inflammatory processes involved in human labor. Suppression of inflammatory pathways by SCFA may be therapeutically beneficial for pregnant women at risk of pathogen-induced preterm delivery.

Background Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death. Methods/design We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups. Discussion Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.

Fetal distress is a very broad term, which can be used in many clinical situations. Although it is difficult to give a precise clinical definition, obstetricians usually use this term to indicate that the fetus is becoming hypoxic. Immediate delivery has to be considered, because neurological damage may occur when the fetal brain is deprived of oxygen.

In order to further evaluate the usefulness of the antiprogestogen, mifepristone, as a cervical ripening agent, a double-blind multicentre study was undertaken of 230 primigravid women with 10–12 weeks amenorrhoea who were randomly assigned to receive either 0 (placebo) or 200 mg of mifepristone 36 hours before surgical pregnancy termination. Fifteen women who did not fulfil all of the selection criteria were excluded from analysis. In the mifepristone group (N = 105) 12 women experienced some pre-operative vaginal bleeding as compared with only one subject in the placebo group (N = 110), but only one of these 12 women described the bleeding as more than her usual menstrual flow. In mifepristone-treated women the cervix was about 1 mm more dilated at operation and further mechanical dilatation was needed less frequently than in placebo-treated controls. High resistance during further mechanical stretching was encountered significantly more often and at a smaller cervical diameter in the placebo group than in the women given mifepristone. Also, dilatation was reported by the operating surgeons to be easier in women given the antiprogestogen. Other significant differences included a shorter operation time, lower peroperative blood loss and less frequent use of analgesic drugs post-operatively in the mifepristone group. Post-operative complications, the duration of post-operative bleeding and the interval to the first menstruation were similar in both groups. The result confirm that the antiprogestogen, mifepristone, is an effective cervical ripening agent which deserves further study in comparison with the currently used methods, i.e. prostaglandins and osmotic dilators.

Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre-eclampsia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay and to determine sensitivity and specificity of the test for pre-eclampsia.Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic.Severely obese (body mass index, BMI40 kg/m(2), n = 194) and lean (BMI25 kg/m(2), n = 78) pregnant women.A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery and stability in maternal plasma samples at 16, 28 and 36 weeks gestation. Pre-eclampsia, defined using International Society for the Study of Hypertension in Pregnancy guidelines; blood pressure; delivery gestation; birthweight.Kisspeptin concentrations were lower in early pregnancy in obese women (P0.001), and in women who later developed pre-eclampsia (P0.05), compared with women with uncomplicated pregnancies. For 16-week plasma kisspeptin in prediction of pre-eclampsia, area under the receiver-operator characteristic curve was 0.80 (P0.01), positive and negative likelihood ratios were 3.0 and 0.2, and test sensitivity and specificity were 85.7 and 71.4%, respectively. In regression analyses, kisspeptin (16 weeks) associated positively with delivery gestation (P0.05) and birthweight (P0.0001), and negatively with 28- and 36-week blood pressure (P0.0001).Kisspeptin concentration in early pregnancy is a promising biomarker for pre-eclampsia and low birthweight but cannot be recommended, in isolation, for universal screening because of inadequate test sensitivity and specificity. Large-scale studies are required to assess its potential in a panel of biomarkers.

The prevalence of obesity in pregnancy is rising exponentially; about 15–20% of pregnant women now enter pregnancy with a BMI which would define them as obese. This paper provides a review of the strong links between obesity and adverse pregnancy outcome which operate across a range of pregnancy complications. For example, obesity is associated with an increased risk of maternal mortality, gestational diabetes mellitus, thromboembolism, pre-eclampsia and postpartum haemorrhage. Obesity also complicates operative delivery; it makes operative delivery more difficult, increases complications and paradoxically increases the need for operative delivery. The risk of the majority of these complications is amplified by excess weight gain in pregnancy and increases in proportion to the degree of obesity, for example, women with extreme obesity have OR of 7·89 for gestational diabetes and 3·84 for postpartum haemorrhage compared to their lean counterparts. The consequences of maternal obesity do not stop once the baby is born. Maternal obesity programmes a variety of long-term adverse outcomes, including obesity in the offspring at adulthood. Such an effect is mediated at least in part via high birthweight; a recent study has suggested that the odds of adult obesity are two-fold greater in babies weighing more than 4 kg at birth. The mechanism by which obesity causes adverse pregnancy outcome is uncertain. This paper reviews the emerging evidence that hyperglycaemia and insulin resistance may both play a role: the links between hyperglycaemia in pregnancy and both increased birthweight and insulin resistance have been demonstrated in two large studies. Lastly, we discuss the nature and rationale for possible intervention strategies in obese pregnant women.

Objective The objective of this study was to compare international trends in pre-eclampsia rates and in overall pregnancy hypertension rates (including gestational hypertension, pre-eclampsia and eclampsia). Design Population data (from birth and/or hospital records) on all women giving birth were available from Australia (two states), Canada (Alberta), Denmark, Norway, Scotland, Sweden and the USA (Massachusetts) for a minimum of 6 years from 1997 to 2007. All countries used the 10th revision of the International Classification of Diseases, except Massachusetts which used the 9th revision. There were no major changes to the diagnostic criteria or methods of data collection in any country during the study period. Population characteristics as well as rates of pregnancy hypertension and pre-eclampsia were compared. Results Absolute rates varied across the populations as follows: pregnancy hypertension (3.6% to 9.1%), pre-eclampsia (1.4% to 4.0%) and early-onset pre-eclampsia (0.3% to 0.7%). Pregnancy hypertension and/or pre-eclampsia rates declined over time in most populations. This was unexpected given that factors associated with pregnancy hypertension such as pre-pregnancy obesity and maternal age are generally increasing. However, there was also a downward shift in gestational age with fewer pregnancies reaching 40 weeks. Conclusion The rate of pregnancy hypertension and pre-eclampsia decreased in northern Europe and Australia from 1997 to 2007, but increased in Massachusetts. The use of a different International Classification of Diseases coding version in Massachusetts may contribute to the difference in trend. Elective delivery prior to the due date is the most likely explanation for the decrease observed in Europe and Australia. Also, the use of interventions that reduce the risk of pregnancy hypertension and/or progression to pre-eclampsia (low-dose aspirin, calcium supplementation and early delivery for mild hypertension) may have contributed to the decline., Article summary Article focus The population prevalence of factors associated with increased and decreased risk of pregnancy hypertension and pre-eclampsia has changed over time, but the impact of these changes is unknown. International comparisons of absolute population rates of pregnancy hypertension and pre-eclampsia are hindered by different diagnostic criteria and methods of data collection. Comparing trends between countries overcomes the difficulties in comparing absolute rates. Key message Pregnancy hypertension and/or pre-eclampsia rates declined over time in northern Europe and Australia, but not Massachusetts (USA). Declining hypertension rates were accompanied by a downward shift in gestational age with fewer pregnancies reaching term, the time when the pregnancy hypertension and pre-eclampsia are most likely to occur. Strengths and limitations of this study Strengths include numerous validation studies indicating that the hypertensive disorders are reliably reported in the population data sets used for the study and the consistency of trends across most countries. Limitations include a different International Classification of Diseases coding version in Massachusetts and lack of available information on clinical interventions.

We aimed to investigate the effects of progesterone on gene expression and function of both myometrium and circulating leukocytes. We recruited women participating in a randomized clinical trial of progesterone to prevent preterm delivery. These participants had a twin pregnancy and were managed in 1 of 2 tertiary referral centers. Participants were treated with progesterone (90 mg vaginally) or placebo from 24 to 34 weeks of pregnancy. The outcome measures were myometrial and leukocyte gene expression and expression of cell surface markers in circulating leukocytes, all quantified ex vivo. Prolonged in vivo administration of progesterone inhibited myometrial expression of connexins 26 and 43, endothelial nitric acid synthase (eNOS), and the prostaglandin receptor EP2 ex vivo. Administration of progesterone also increased numbers of circulating neutrophils while decreasing lymphocyte proportions and decreasing neutrophil CD11b expression. The observed effects of prolonged in vivo administration of progesterone will minimize the ability of the uterus to contract as a synctium and the ability of peripheral blood leukocytes to migrate into the myometrium during parturition. We suggest that these are putative mechanisms by which progesterone might prevent preterm birth in women at high risk.

International audience; Human parturition is an inflammatory event, modulated and influenced by a host of other environmental and physiological processes, including the endocrine hormones. Complex bidirectional communication occurs between the two systems to bring about some of the changes that are seen in labour, an event that is not yet fully understood. Preterm birth is a major problem in obstetrics and neonatology, with dysfunctional labour or prolonged pregnancy also making increasingly significant contributions to maternal morbidity. With better understanding of normal and abnormal parturition we may be able to develop novel ways of treating these complications of pregnancy and reduce maternal and neonatal morbidity and mortality. This review discusses the crucial role that endocrine-immune interaction plays in the process of labour and in the processes of abnormal and preterm labour. We propose that amongst these complex interactions it is the immune system that is the driving force behind human parturition.

In a recent survey, 24.1% of Scottish women were classified as obese and 3.5% as severely obese (1) . Maternal obesity has short- and longterm detrimental effects on mothers’ and babies’ health (2) . However, evidence is limited for best diet and gestational weight management advice for severely obese women. We aimed at assessing food intake and knowledge in severely obese (BMI > 40 kg/m 2 ) and lean (BMI 20–25 kg/m 2 ) pregnant women. One hundred and two severely obese and fifty lean (BMI 43.5 (0.5) v. 22.6 (0.2) kg/m 2 , P < 0.001) pregnant women were recruited from a cohort study of severe obesity in pregnancy at Royal Infirmary, Edinburgh, UK. Ethical approval and written informed consent were obtained. Obese women were advised about healthy eating and weight maintenance during pregnancy. Food intake (total energies, macroand micronutrients) was assessed during early (12–20 weeks gestation) and late (28–36 weeks) pregnancy by validated FFQ (3) . Thirty-two women from each group completed a food diary for 4 d (3 week days and 1 weekend day). A subgroup completed the General Nutrition Knowledge Questionnaire (4) (n 69 obese, n 47 lean) and a Nutrition Appetite Questionnaire (5) (n 37 obese, n 29 lean). Serial anthropometry was performed. Data were analysed using SPSS version 14.0. Data are mean (SEM). Obese women gained significantly less weight than lean women (6.09 (0.54) v. 10.56 (0.65) kg, P < 0.001) between booking and 36 weeks gestation. Total energy intake was higher in obese compared with lean during early pregnancy ((11422.32 (548.104) v. 9886.792 (548.104) kJ/d) (2730 (131) v. 2363 (95) kcal/d), P < 0.05) but not different during late pregnancy ((9840.768 (389.112) v. 10334.48 (510.448) kJ/d) (2352 (93) v. 2470 (122) kcal/d), P = NS). Obese women reported proportionally higher intake of sugars, saturated fat, dietary cholesterol but lower fibre, folic acid, Fe, Ca and vitamin D (P < 0.05) than lean in both early and late pregnancy. Both groups failed to meet recommended values for key nutrients in pregnancy including Ca, Fe, folic acid and vitamin D. Both groups reported significantly lower intake of total energy by food diary compared with FFQ (obese: 6698.584 (347.272) v. 10489.288 (711.28) kJ/d; lean: 7313.632 (271.96) v. 10727.776 (514.632) kJ/d) (obese: 1601 (83) v. 2,507 (170) kcal/d; lean: 1748 (65) v. 2564 (123) kcal/d) and this pattern was similar with all other nutrients (range 23–85% lower, depending on nutrient, all P < 0.05). Obese women reported lower appetite than lean in both early (20.9 (0.5) v. 23.0 (0.5), P < 0.01) and late (20.8 (0.6) v. 23.4 (0.4) P < 0.01) pregnancy. Obese women also had lower scores in general nutrition knowledge (67 (1.9) v. 80 (1.7) marks, P < 0.05) than the lean group. Results remained significant after controlling for the education level. In summary, severely obese pregnant women had significantly less gestational weight gain than lean. It is not known whether this is due to the reduction in energy intake during pregnancy, the reported lower appetite, or due to the dietary advice given and the intense care and attention they received during participation in the study. Severely obese pregnant women ate a more unhealthy diet, rich in saturated fats and sugars and had lower scores in general nutrition knowledge. Both groups reported lower energy intake in the food diary compared with FFQ responses, suggesting the possibility of under-reporting. The failure to meet recommendations for key nutrients in pregnancy in both groups suggests dietary education is necessary among women planning pregnancy.

Preterm birth (PTB) is estimated to account for 6-10% of all births worldwide with 13 million PTBs occurring annually and 1 million resulting in death. The diagnosis of spontaneous preterm labor and accurate prediction of preterm delivery is notoriously difficult. Identification of effective risk assessment markers can potentially improve outcomes by enabling targeted therapy while allowing efficient use of resources and avoiding unnecessary interventions. Advances in perinatal medicine have not reduced PTB and effective measures that improve outcome are yet to be established. However, considerable progress has been made in the development of accurate methods (fetal fibronectin and cervical length assessment) to predict PTB in both symptomatic and asymptomatic high-risk women. The excellent negative predictive value of fFN has the ability to facilitate decision-making regarding admission, in utero transfer, administration of antenatal corticosteroids and/or tocolysis and has been shown to be cost-effective. This review describes the European perspective on the use of fFN and describes ongoing European clinical studies, which are appropriately designed with meaningful endpoints, which will undoubtedly facilitate a better understanding of test accuracy and cost-effectiveness within different populations.

Since the discovery of the structure and function of steroids over 60 years ago, it has long been recognized that synthetic antagonists of the natural hormones would have potential therapeutic uses. Antagonists of mineralocorticoids, androgens and oestrogens, for example spironolactine, cyproterone, flutamide and tamoxifen, have already found a place in the management of hormone dependent conditions. In 1982, chemists at Roussel UCLAF announced that they had synthesized mifepristone (RU486) 17β-hydroxy-11(p-(dimethylamino)phenyl)-17-(1-propynyl) estra-411, 9-dien-3-one) a derivative of norethindrone which had potent antiprogestogenic as well as antiglucocorticoid activity. Although it was immediately realised that this compound would potentially have wide clinical application, its development in the last 10 years has been dominated by its abortifacient action. In the original clinical report by Herrman and colleagues it was shown that bleeding occurred when it was given to female volunteers in the second half of the menstrual cycle. In addition, complete abortion occurred in eight of 11 women who took the drug in the early weeks of pregnancy. These findings, which demonstrated that mifepristone could be used as the basis of a medical method of inducing abortion, were immediately made the focus of groups opposed to abortion on moral grounds. Experience over the last 10 years has confirmed the promise of these early studies and mifepristone, in combination with a suitable prostaglandin, is now licensed in France, UK and Sweden for use as a medical method of inducing abortion in early pregnancy.

BACKGROUND: Induction of labour is carried out for a variety of indications and using a range of methods. For women at low risk of pregnancy complications, some methods of induction of labour or cervical ripening may be suitable for use in outpatient settings. OBJECTIVES: To examine pharmacological and mechanical interventions to induce labour or ripen the cervix in outpatient settings in terms of effectiveness, maternal satisfaction, healthcare costs and, where information is available, safety. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials examining outpatient cervical ripening or induction of labour with pharmacological agents or mechanical methods. Cluster trials were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed evidence using the GRADE approach. MAIN RESULTS: This updated review included 34 studies of 11 different methods for labour induction with 5003 randomised women, where women received treatment at home or were sent home after initial treatment and monitoring in hospital. Studies examined vaginal and intracervical prostaglandin E₂ (PGE₂), vaginal and oral misoprostol, isosorbide mononitrate, mifepristone, oestrogens, amniotomy and acupuncture, compared with placebo, no treatment, or routine care. Trials generally recruited healthy women with a term pregnancy. The risk of bias was mostly low or unclear, however, in 16 trials blinding was unclear or not attempted. In general, limited data were available on the review's main and additional outcomes. Evidence was graded low to moderate quality. 1. Vaginal PGE₂ versus expectant management or placebo (5 studies) Fewer women in the vaginal PGE₂ group needed additional induction agents to induce labour, however, confidence intervals were wide (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.27 to 0.99; 150 women; 2 trials). There were no clear differences between groups in uterine hyperstimulation (with or without fetal heart rate (FHR) changes) (RR 3.76, 95% CI 0.64 to 22.24; 244 women; 4 studies; low‐quality evidence), caesarean section (RR 0.80, 95% CI 0.49 to 1.31; 288 women; 4 studies; low‐quality evidence), or admission to a neonatal intensive care unit (NICU) (RR 0.32, 95% CI 0.10 to 1.03; 230 infants; 3 studies; low‐quality evidence). There was no information on vaginal birth within 24, 48 or 72 hours, length of hospital stay, use of emergency services or maternal or caregiver satisfaction. Serious maternal and neonatal morbidity or deaths were not reported. 2. Intracervical PGE₂ versus expectant management or placebo (7 studies) There was no clear difference between women receiving intracervical PGE₂ and no treatment or placebo in terms of need for additional induction agents (RR 0.98, 95% CI 0.74 to 1.32; 445 women; 3 studies), vaginal birth not achieved within 48 to 72 hours (RR 0.83, 95% CI 0.68 to 1.02; 43 women; 1 study; low‐quality evidence), uterine hyperstimulation (with FHR changes) (RR 2.66, 95% CI 0.63 to 11.25; 488 women; 4 studies; low‐quality evidence), caesarean section (RR 0.90, 95% CI 0.72 to 1.12; 674 women; 7 studies; moderate‐quality evidence), or babies admitted to NICU (RR 1.61, 95% CI 0.43 to 6.05; 215 infants; 3 studies; low‐quality evidence). There were no uterine ruptures in either the PGE₂ group or placebo group. There was no information on vaginal birth not achieved within 24 hours, length of hospital stay, use of emergency services, mother or caregiver satisfaction, or serious morbidity or neonatal morbidity or perinatal death. 3. Vaginal misoprostol versus placebo (4 studies) One small study reported on the rate of perinatal death with no clear differences between groups; there were no deaths in the treatment group compared with one stillbirth (reason not reported) in the control group (RR 0.34, 95% CI 0.01 to 8.14; 77 infants; 1 study; low‐quality evidence). There was no clear difference between groups in rates of uterine hyperstimulation with FHR changes (RR 1.97, 95% CI 0.43 to 9.00; 265 women; 3 studies; low‐quality evidence), caesarean section (RR 0.94, 95% CI 0.61 to 1.46; 325 women; 4 studies; low‐quality evidence), and babies admitted to NICU (RR 0.89, 95% CI 0.54 to 1.47; 325 infants; 4 studies; low‐quality evidence). There was no information on vaginal birth not achieved within 24, 48 or 72 hours, additional induction agents required, length of hospital stay, use of emergency services, mother or caregiver satisfaction, serious maternal, and other neonatal, morbidity or death. No substantive differences were found for other comparisons. One small study found that women who received oral misoprostol were more likely to give birth within 24 hours (RR 0.65, 95% CI 0.48 to 0.86; 87 women; 1 study) and were less likely to require additional induction agents (RR 0.60, 95% CI 0.37 to 0.97; 127 women; 2 studies). Women who received mifepristone were also less likely to require additional induction agents (average RR 0.59, 95% CI 0.37 to 0.95; 311 women; 4 studies; I² = 74%); however, this result should be interpreted with caution due to high heterogeneity. One trial each of acupuncture and outpatient amniotomy were included, but few review outcomes were reported. AUTHORS' CONCLUSIONS: Induction of labour in outpatient settings appears feasible and important adverse events seem rare, however, in general there is insufficient evidence to detect differences. There was no strong evidence that agents used to induce labour in outpatient settings had an impact (positive or negative) on maternal or neonatal health. There was some evidence that compared to placebo or no treatment, induction agents administered on an outpatient basis reduced the need for further interventions to induce labour, and shortened the interval from intervention to birth. We do not have sufficient evidence to know which induction methods are preferred by women, the interventions that are most effective and safe to use in outpatient settings, or their cost effectiveness. Further studies where various women‐friendly outpatient protocols are compared head‐to‐head are required. As part of such work, women should be consulted on what sort of management they would prefer.

The purpose of this pilot study was to determine the role of foetal fibronectin (fFN) testing in women presenting to hospital with symptoms of preterm labour in reducing the hospital admissions, without significantly increasing the risk of preterm birth and neonatal respiratory distress syndrome. Women with symptoms of preterm labour were assigned randomly to receive fFN (n = 44) or to preterm labour management without fFN (n = 44). In the testing arm, the result of the test was revealed to the clinician. Clinical outcomes were compared in the two groups. The time period covered by the randomised controlled trial (RCT) was from December 2007 to March 2009. The RCT was conducted in two large maternity units in the west of Scotland, one in Glasgow the other in Ayrshire. All the women with fibronectin positive got admitted while only 32.4% of the fibronectin negatives were admitted (P = 0.002). There was a significant difference in the mean length of stay between the fibronectin positives which was 47.17 h, and the negatives which was 12.9 h (P = 0.018). Overall the control and testing arms did not differ in respect to admissions and length of stay. 5 out of 7 positives and 11 out of 37 negatives had corticosteroids (P = 0.089). 2 out of 7 positives and 1 out of 37 negatives had tocolytics (P = 0.073). Those who had the fFN test done were less likely to be admitted in the hospital and had a shorter length of stay, without any increase in the adverse maternal or foetal effects, avoiding unnecessary admissions.

The onset of labour is associated with inflammatory cascades in the uteroplacental unit, and these are prematurely activated in preterm labour. Infection can induce an inflammatory response, which results in premature onset of the pro-inflammatory parturient cascades and preterm delivery. We have become interested in two proteins called prokineticins and the role they may play in labour and its premature onset. Prokineticin 1 and 2 bind to two G-protein coupled receptors, called prokineticin receptor 1 and 2. Expression of the prokineticins and their receptors is elevated in the uteroplacental unit during labour and they can induce expression of a host of genes known to be important in initiating the inflammatory and contractile events of labour. Prokineticins have also been shown to directly induce contractility of smooth muscles. Analysing the promoter regions of the prokineticins and their receptors highlights their potential regulation by pathways activated by infectious agents. Hence, we propose that infection can result in premature activation of prokineticin expression and signalling in the uteroplacental unit and this initiates a premature inflammatory and contractile cascade leading to preterm birth. Antagonism of prokineticin action may provide a suitable therapy for preterm labour that targets both inflammation and contractile pathways.

Despite intensive research over the last few decades, the control of labour in human pregnancy is not clearly understood. Parturition involves both the generation of uterine activity and softening and dilation of the uterine cervix. In this article the endocrine, paracrine and immunological regulators of these mechanisms and the relative importance of these factors in the physiology of parturition will be reviewed.

Objective To determine the efficacy of a new dose regimen of vaginal gemeprost (l mg every 6 h up to three doses) in induction of abortion in women ≤56 days gestation, and to compare this regimen with mifepristone (200–600 mg) followed 48 h later by a single dose of gemeprost (l mg). Design Two separate protocols, with 50% of the subjects randomized to one or other protocol. Setting The Royal Infirmary of Edinburgh, Scotland, UK Subjects 301 referred by their general practitioner or local family planning clinic, requesting termination of pregnancy at ≤56 days amenorrhoea. Interventions Ongoing pregnancies and incomplete abortions were terminated surgically. Main outcome measures Number of complete abortions, analgesic requirements and bleeding pattern following treatment. Results Complete abortion occurred in 87% of women treated with gemeprost alone and 98% of women treated with mifepristone and gemeprost (P=0.0004). Analgesic requirements were greater in the group treated with gemeprost alone, compared with the group treated with mifepristone and gemeprost (P=0.0001). Conclusion The new dose regimen of gemeprost can be used for early induced abortion, but the use of mifepristone and gemeprost has several advantages over the use of gemeprost alone.

We hypothesized that the priming and activation of maternal leukocytes in peripheral blood is a key component of parturition, and that inappropriate preterm priming of leukocytes might initiate preterm labour and delivery. The purpose of this study was to characterize peripheral blood leukocyte activation during human term and preterm labour. We obtained blood samples from pregnant women at term and preterm, both in labour and not in labour. Leukocytes were characterized according to cell subtype and cell surface marker expression. Addition- ally, we quantified leukocyte cytokine mRNA production, migratory ability and reactive oxygen species production of neutrophils and macro- phages. We found that both term and preterm labour were associated with an increase in monocyte and neutrophil proportion or number—neutrophil migratory ability and cell surface marker expression indicating activation. Messenger RNA expression of IL-1b and IL-8, MCP-1 and TLR-2 was also increased. We conclude that leukocytes in peripheral blood are primed in preparation for activation during term and preterm labour, and that this may contribute to the pathophysiological events of parturition. These data may lead to novel therapies and diagnostic tools for the prevention and/or diagnosis of preterm birth.

Objective To determine whether isosorbide mononitrate (IMN), self-administered vaginally by women at home, improves the process of induction of labour. Design Randomised double blind placebo-controlled trial. Setting Large UK maternity hospital. Population or Sample Nulliparous women with a singleton pregnancy, cephalic presentation ≥37 weeks gestation, requiring cervical ripening prior to induction of labour. Methods IMN (n = 177) or placebo (n = 173) self-administered vaginally at home at 48, 32 and 16 hours prior to the scheduled time of admission for induction. Main outcome measures Admission to delivery interval and women’s experience of induction of labour. Results IMN did not shorten the admission to delivery interval as compared with placebo [mean difference of −1.6 hours (95% CI −5.1,1.9, P = 0.37)], despite being more effective than placebo in inducing a change in Bishop score [mean difference of 0.65 (95% CI 0.14,1.17, P = 0.013)]. While both groups found the overall experience of home treatment to be positive, (mean score of 3.8/10 ± 2.3/10 for the IMN group, where 1 = extremely good and 10 = not at all good) women in the placebo group found it marginally more positive than those in the IMN group (just over half a unit on a 10-point scale, P = 0.043). There were no differences between the groups in the pain or anxiety experienced or willingness to take the treatment in a subsequent pregnancy. Conclusions IMN self-administered vaginally at home does not shorten admission to delivery interval despite a significant effect on cervical ripeness assessed using the Bishop score. However, women report positive views on cervical ripening at home, and the setting deserves further investigation.

Inflammation is a process by which tissues respond to various insults. It is characterized by upregulation of chemokines, cytokines, and pattern recognition receptors that sense microbes and tissue breakdown products. During pregnancy, the balance of Th1 (cell-mediated immunity) and Th2 (humoral immunity) cytokines is characterized by an initial prevalence of Th2 cytokines, followed by a progressive shift toward Th1 predominance late in gestation, that when is abnormal, may initiate and intensify the cascade of inflammatory cytokine production involved in adverse pregnancy outcomes. Maternal and placental hormones may affect the inflammatory pathway. Hypoxia and the innate immune response are 2 adaptive mechanisms by which organisms respond to perturbation in organ function, playing a major role in spontaneous abortion, intrauterine growth restriction, preeclampsia, and preterm delivery. The interaction between tissue remodeling factors, like matrix metalloproteinases, and vasoactive/hemostatic factors, like prostaglandin and coagulation factors, mediates this adaptive response.

A combination of the antiprogestagen mifepristone and an exogenous prostaglandin given by intramuscular injection or intravaginal pessary is a highly effective means of inducing abortion in early pregnancy. However, the search for a stable oral prostaglandin preparation has been largely unsuccessful. The effect of misoprostol, an orally active prostaglandin used to treat peptic ulcer, on uterine contractility was investigated in 33 women in early pregnancy (under 56 days' amenorrhoea). After administration of misoprostol in doses ranging from 200 micrograms to 600 micrograms, there was a significant increase in uterine pressure. In a second group of women who were given 200-1000 micrograms misoprostol 48 h after the administration of 200 mg mifepristone, there was a significant increase in the amplitude and frequency of uterine contractions. Complete abortion took place in 18 of the 21 women who received misoprostol after mifepristone, but in only 2 of 40 women given misoprostol alone. Our findings show that misoprostol increases uterine activity in early pregnancy and suggest that, in combination with mifepristone, it may be a highly effective method of inducing therapeutic abortion.

At term, amniotic fluid contents may mediate the onset of labor through the activation of amniotic fluid macrophages and their migration into the myometrium. To test this concept, the authors examine the histological changes that occur in myometrial biopsies at term prior to (n = 53) and during (n = 15) labor. Biopsies were stained with an antimacrophage antibody, anti-CD34 (endothelial cells), and anti-caspase 3 (apoptotic cells). The samples showed a variable inflammatory infiltrate of neutrophils and macrophages, with a greater infiltrate in the samples obtained during labor (P < .001, Fisher exact test). Prior to labor, there were prominent changes in the myometrial fibers that reflected shearing, shrinkage, edema, and particularly apoptosis; endothelial cells of thin-walled vessels prominent in the biopsies displayed marked nuclear biotinylation, and the vascular lumen contained fibrin and platelet thrombi, microparticles, desquamated endothelial cells, amniotic squamous cells, and mucoid material. These changes were also present in samples obtained during labor. In an additional 10 patients in labor with male fetuses, myometrial samples were examined for the presence of macrophages carrying a Y chromosome indicative of a fetal origin, but none were observed. These findings suggest that endothelial cell damage and amniotic fluid embolism are very common at term prior to clinical labor and provide a mechanism by which surfactant protein A and phospholipids present in the amniotic fluid may access myometrial cells and provoke the inflammatory response that occurs during parturition. The authors' studies give no support to the suggestion that fetal macrophages might invade the human myometrium at term.

Increasing evidence suggests that parturition is an inflammatory process. In this brief overview, inflammatory events occurring in association with parturition, and the mechanism by which they may contribute to labour and delivery will be discussed. Mention will be made of how this information may be of use in regulating the timing and the onset of parturition.