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The aim of this study was to assess a new device (Tydeman Tube) designed to facilitate delivery of the impacted foetal head at caesarean section. Standard digital vaginal technique and the Tydeman Tube were each used to elevate the foetal head on a validated full dilatation caesarean simulator. Greater elevation of the foetal head was achieved with the Tydeman Tube than digital technique (mean difference +9.1 mm, p < 0.001). Although greater force was applied to achieve this elevation (mean difference +0.42 Kgf, p < 0.001), the force was spread over a greater area (6.97 cm 2 versus 2.0 cm 2 ). Therefore, mean pressures applied to the foetal head were lower (mean difference -2.3 Kg cm 2 , p < 0.001). The first uses of the Tydeman Tube in clinical practice were described. Clinicians found it easy to use and effective (mean score 7.7/10). The Tydeman Tube is an effective tool for delivering the impacted foetal head on a simulator and its initial use in clinical practise has proved positive.

Objective: To determine the effect of a low-lying placenta on the concentration of quantitative fetal fibronectin (qfFN) in the cervicovaginal fluid (CVF), and predictive accuracy for spontaneous preterm birth in asymptomatic high-risk women (18  +   0 -24  +   0 weeks gestation)., Methods: Median concentrations of qfFN were compared in women who had a low-lying placenta, covering the cervical os (n = 61) to matched controls (n= 61) without a low-lying placenta. Proportions of women with raised qfFN concentrations (>10 ng/ml), and false positive and negative rates (FPR and FNR) for spontaneous preterm delivery were also compared., Results: The median concentration of qfFN in women with low-lying placenta was 5.0 ng/mL, compared with 6.0 ng/mL in controls. Proportion of women with raised levels (>10 ng/mL), positive levels (>50 ng/mL) and very high levels (>200 ng/mL) were similar in both groups (62.3% versus 59.0%, 16.3% versus 22.0% and 6.5% versus 4.9%, p > 0.05 for all thresholds). The FPR and FNR rate for delivery before 34 and 37 weeks were also comparable (FPR 90.0% versus 85.7% and 80.0% versus 78.6%; FNR 5.8% versus 4.3% and 9.8% versus 8.5%)., Conclusions: CVF qfFN concentrations in asymptomatic high-risk women are not affected by the presence of a low-lying placenta.

Objective: To examine the monitoring, management, and outcomes of pituitary tumors in pregnancy., Methods: A national, prospective, observational, population-based case series study was conducted in all U.K. consultant-led obstetric units over 3 years using the U.K. Obstetric Surveillance System. To evaluate rates of adverse pregnancy outcomes, women with a macroprolactinoma (10 mm or greater) or nonfunctioning pituitary adenoma, diagnosed before or during pregnancy, were compared with two comparison groups: 1) a U.K. Obstetric Surveillance System cohort with singleton (n=2,205) or twin (n=27) pregnancy; and 2) data from the Office of National Statistics (n=2,703,102). Main outcome measures were the incidence, management, and frequency of adverse maternal and offspring outcomes of pituitary tumors in pregnancy., Results: There were 71 confirmed cases of pituitary tumors in pregnancy (49 macrolactinoma, 16 nonfunctioning adenomas, three acromegaly, three Cushing's disease). The women with pituitary tumors were 4 years older than comparison women (P<.001). None of the nine women treated with surgery or radiotherapy before pregnancy had symptomatic tumor expansion. This occurred in 6 of 40 women with macroprolactinomas and one of seven nonfunctioning adenomas diagnosed before conception and in three of five women with nonfunctioning adenomas diagnosed in pregnancy. Two women had pituitary apoplexy, both of whom also had symptoms of expansion of tumor or surrounding pituitary tissue. To within the level of accuracy possible, there was no evidence that pituitary tumors were associated with adverse pregnancy outcomes (pregnancy-induced hypertension, preeclampsia, preterm labor, stillbirth). Women with nonfunctioning adenomas were more likely to have cesarean delivery compared with women in a control group (relative risk 2.06, confidence interval 1.26-3.36, P=.035)., Conclusion: The majority of women with macroprolactinomas and nonfunctioning adenomas have good pregnancy outcomes. Nonfunctioning pituitary adenomas occur more commonly in pregnancy than previously thought and can present de novo with symptoms of pituitary expansion in pregnancy.

Objective: Spontaneous preterm birth is the leading cause of neonatal morbidity and mortality. Cervicovaginal fetal fibronectin (fFN) has enhanced prediction of preterm birth and, more recently, quantified results have become available so that management can planned more effectively and targeted to individual women. Manufacture guidelines stipulate that fetal fibronectin (fFN) samples should be discarded in the presence of moderate to heavy vaginal bleeding but there hasn't yet been any formal investigation into the effect of blood staining on fetal fibronectin concentration and subsequent preterm birth prediction. The objective for this study was to determine the impact of blood stained swabs on quantitative fetal fibronectin (qfFN) concentration and prediction of spontaneous preterm birth (sPTB) in asymptomatic high-risk women., Study Design: Predefined blinded sub-analysis of a larger prospective study of qfFN in asymptomatic women at high-risk of preterm labour. Women with and without blood stained swabs were matched for gestational age at testing and delivery, risk factors and cervical length measurement., Results: Median fFN concentration in blood stained swabs (n=58) was 66ng/ml vs. 7.5ng/ml in the controls (n=58) (p<0.0001). At ≥50ng/ml threshold the false positive ratio (FPR) in blood stained was 25/33 (75.8%) vs. 8/15 (53%) in controls, (risk difference 22.4; -6.8 to 51.6, p=0.18). At ≥50ng/ml threshold the false-negative ratio (FNR) in blood stained was 2/25 (8.0%) vs. 1/43 (2.3%) in controls (risk difference -5.7; -17.2 to 5.9, p=0.55). At each threshold 10, 50 and 200ng/ml blood stained swabs had higher sensitivity but lower specificity for predicting preterm birth. Receiver Operating Characteristic (ROC) curve, the strongest global measure of test performance, for prediction of delivery at <34 weeks gestation was similar in blood stained vs. control groups. (0.78 vs. 0.84) in blood stained vs. control groups respectively., Conclusion: Blood stained swabs have elevated qfFN concentrations but may still have predictive value, and clinical utility. Very low fFN values (<10ng/ml) are especially reassuring and indicate lower risk of delivery than non-blood stained swabs. The higher false positive rate must be noted and explained to the patient., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Objective: To determine the normal ranges of vital signs, including blood pressure (BP), mean arterial pressure (MAP), heart rate (HR) and shock index (SI) (HR/systolic BP), in the immediate postpartum period to inform the development of robust obstetric early warning scores., Study Design: We conducted a secondary analysis of a prospective observational cohort study evaluating vital signs collected within one hour following delivery in women with estimated blood loss (EBL) <500ml (316 women) delivering at a UK tertiary centre over a one-year period. Simple and multiple linear regression were used to explore associations of demographic and obstetric factors with SI., Results: Median (90% reference range) was 120 (100-145) for systolic BP, 75 (58-90) for diastolic BP, 90 (73-108) for MAP, 81 (61-102) for HR, and 0.66 (0.52-0.89) for SI. Third stage Syntometrine® administration was associated with a 0.03 decrease in SI (p = 0.035) and epidural use with a 0.05 increase (p = 0.003). No other demographic or obstetric factors were associated with a change in shock index in this cohort., Conclusion: This is the first study to determine normal ranges of maternal BP, MAP, HR and SI within one hour of birth, a time of considerable haemodynamic adjustment, with minimal effect of demographic and obstetric factors demonstrated. The lower 90% reference point for systolic BP and upper 90% reference point for HR correspond to triggers used to recognise shock in obstetric practice, as do the upper 90% reference points for systolic and diastolic BP for obstetric hypertensive triggers. The SI upper limit of 0.89 in well postpartum women supports current literature suggesting a threshold of 0.9 as indicating increased risk of adverse outcomes., Competing Interests: The authors have declared that no competing interests exist.

All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0-18+6 weeks' gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68-0.74). This increased to 0.77 (95%CI 0.73-0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74-0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LP reports a grant from Abbott Nutrition, outside the submitted work. KMG reports reimbursement for speaking from Nestle Nutrition Institute, grants from Abbot Nutrition and Nestec, outside the submitted work. In addition, KMG has a number of patents pending that are not directly related to this work (Phenotype prediction, Predictive use of CpG methylation and Maternal Nutrition Composition). DAL has received research support from Roche Diagnostics and Medtronic, as well as public and charitable funders, for research that is not central to that presented in this paper. This does not alter our adherence to PLOS ONE policies on sharing data and materials. SLW, ALB, SMN, EON, SCR, NS, PTS, MCV, MW and DP have no competing interests to report.

Background: Understanding dietary patterns in obese pregnant women will inform future intervention strategies to improve pregnancy outcomes and the health of the child. The aim of this study was to investigate the effect of a behavioral intervention of diet and physical activity advice on dietary patterns in obese pregnant woman participating in the UPBEAT study, and to explore associations of dietary patterns with pregnancy outcomes., Methods: In the UPBEAT randomized controlled trial, pregnant obese women from eight UK multi-ethnic, inner-city populations were randomly assigned to receive a diet/physical activity intervention or standard antenatal care. The dietary intervention aimed to reduce glycemic load and saturated fat intake. Diet was assessed using a food frequency questionnaire (FFQ) at baseline (15 +0 -18 +6 weeks' gestation), post intervention (27 +0 -28 +6 weeks) and in late pregnancy (34 +0 -36 +0 weeks). Dietary patterns were characterized using factor analysis of the baseline FFQ data, and changes compared in the control and intervention arms. Patterns were related to pregnancy outcomes in the combined control/intervention cohort (n = 1023)., Results: Four distinct baseline dietary patterns were defined; Fruit and vegetables, African/Caribbean, Processed, and Snacks, which were differently associated with social and demographic factors. The UPBEAT intervention significantly reduced the Processed (-0.14; 95% CI -0.19, -0.08, P <0.0001) and Snacks (-0.24; 95% CI -0.31, -0.17, P <0.0001) pattern scores. In the adjusted model, baseline scores for the African/Caribbean (quartile 4 compared with quartile 1: OR = 2.46; 95% CI 1.41, 4.30) and Processed (quartile 4 compared with quartile 1: OR = 2.05; 95% CI 1.23, 3.41) patterns in the entire cohort were associated with increased risk of gestational diabetes., Conclusions: In a diverse cohort of obese pregnant women an intensive dietary intervention improved Processed and Snack dietary pattern scores. African/Caribbean and Processed patterns were associated with an increased risk of gestational diabetes, and provide potential targets for future interventions., Trial Registration: Current controlled trials; ISRCTN89971375.

Background: Clinically, once a woman has been identified as being at risk of spontaneous preterm birth (sPTB) due to a short cervical length, a decision regarding prophylactic treatment must be made. Three interventions have the potential to improve outcomes: cervical cerclage (stitch), vaginal progesterone and cervical pessary. Each has been shown to have similar benefit in reduction of sPTB, but there have been no randomised control trials (RCTs) to compare them., Methods: This open label multi-centre UK RCT trial, will evaluate whether the three interventions are equally efficacious to prevent premature birth in women who develop a short cervix (<25 mm on transvaginal ultrasound). Participants will be asymptomatic and between 14 +0 and 23 +6 weeks' gestation in singleton pregnancies. Eligible women will be randomised to cervical cerclage, Arabin pessary or vaginal progesterone (200 mg once daily) (n = 170 women per group). The obstetric endpoints are premature birth rate <37 weeks' of gestation (primary), 34 weeks and 30 weeks (secondary outcomes) and short-term neonatal outcomes (a composite of death and major morbidity). It will also explore whether intervention success can be predicted by pre-intervention biomarker status., Discussion: Preterm birth is the leading cause of perinatal morbidity and mortality and a short cervix is a useful way of identifying those most at risk. However, best management of these women has presented a clinical conundrum for decades. Given the promise offered by cerclage, Arabin pessary and vaginal progesterone for prevention of preterm birth in individual trials, direct comparison of these prophylactic interventions is now essential to establish whether one treatment is superior. If, as we hypothesise, the three interventions are equally efficacious, this study will empower women to make a choice of treatments based on personal preference and quality of life issues also explored by the study. Our exploratory analysis into whether the response to intervention is related to the pre-intervention biomarker status further our understanding of the pathophysiology of spontaneous preterm birth and help focus future research questions., Trial Registration: EudraCT Number: 2015-000456-15 . Registered 11th March 2015.

Objective: To model the resource implications of placental growth factor (PlGF) testing in women with suspected pre-eclampsia prior to 35 weeks' gestation as part of a management algorithm, compared with current practice., Methods: Data on resource use from 132 women with suspected pre-eclampsia prior to 35 weeks' gestation, enrolled in a prospective observational cohort study evaluating PlGF measurement within antenatal assessment units within two UK consultant-led maternity units was extracted by case note review. A decision analytic model was developed using these data to establish the budget impact of managing women with suspected pre-eclampsia for two weeks from the date of PlGF testing, using a clinical management algorithm and reference cost tariffs. The main outcome measures of resource use (numbers of outpatient appointments, ultrasound investigations and hospital admissions) were correlated to final diagnosis and used to calculate comparative management regimes., Results: The mean cost saving associated with the PlGF test (in the PlGF plus management arm) was £35,087 (95% CI -£33,181 to -£36,992) per 1,000 women. This equated to a saving of £582 (95% CI -552 to -£613) per woman tested. In 94% of iterations, PlGF testing was associated with cost saving compared to current practice., Conclusions: This analysis suggests PlGF used as part of a clinical management algorithm in women presenting with suspected pre-eclampsia prior to 35 weeks' gestation could provide cost savings by reducing unnecessary resource use. Introduction of PlGF testing could be used to direct appropriate resource allocation and overall would be cost saving., Competing Interests: Professor Shennan received honoraria for speaking at an Alere-sponsored symposium at an international conference in 2013 and was a paid consultant for Alere, Roche, and Perkin Elmer up to 2013. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Congophilia indicates the presence of amyloid protein, which is an aggregate of misfolded proteins, that is implicated in the pathophysiologic condition of preeclampsia. Recently, urinary congophilia has been proposed as a test for the diagnosis and prediction of preeclampsia., Objectives: The purpose of this study was to determine whether urine congophilia is present in a cohort of women with preeclampsia and in pregnant and nonpregnant women with renal disease., Study Design: With the use of a preeclampsia, chronic hypertension, renal disease, and systemic lupus erythematosus cohort, we analyzed urine samples from healthy pregnant control subjects (n = 31) and pregnant women with preeclampsia (n = 23), gestational hypertension (n = 10), chronic hypertension (n = 14), chronic kidney disease; n = 28), chronic kidney disease with superimposed preeclampsia (n = 5), and chronic hypertension and superimposed preeclampsia (n = 12). Samples from nonpregnant control subjects (n = 10) and nonpregnant women with either systemic lupus erythematosus with (n = 25) and without (n = 14) lupus nephritis were analyzed. For each sample, protein concentration was standardized before it was mixed with Congo Red, spotted to nitrocellulose membrane, and rinsed with methanol. The optical density of the residual Congo Red stain was determined; Congo red stain retention was calculated, and groups were compared with the use of the Mann-Whitney test or Kruskal-Wallis analysis of Variance test, as appropriate., Results: Congophilia was increased in urine from women with preeclampsia (median Congo red stain retention, 47%; interquartile range, 22-68%) compared with healthy pregnant control subjects (Congo red stain retention: 16%; interquartile range, 13-21%; P = .002), women with gestational hypertension (Congo red stain retention, 20%; interquartile range, 13-27%; P = .008), or women with chronic hypertension (Congo red stain retention, 17%; interquartile range, 12-28%; P = .01). There were no differences in Congo red retention between pregnant women with chronic hypertension and normal pregnant control subjects (Congo red stain retention, 17% [interquartile range, 12-28%] vs 16% [interquartile range, 13-21%], respectively; P = .72). Congophilia was present in pregnant women with chronic kidney disease (Congo red stain retention, 32%; interquartile range, 14-57%), being similar to values found in women with preeclampsia (P = .22) and for women with chronic kidney disease and superimposed preeclampsia (Congo red stain retention, 57%; [interquartile range, 29-71%; P = .18). Nonpregnant women with lupus nephritis had higher congophilia levels compared with nonpregnant female control subjects (Congo red stain retention, 38% [interquartile range, 17-73%] vs 9% [7-11%], respectively; P < .001) and nonpregnant women with systemic lupus erythematosus without nephritis (Congo red stain retention, 38% [interquartile range, 17-73%] vs 13% [interquartile range, 11-17%], respectively; P = .001). A significant positive correlation was observed between congophilia and protein:creatinine ratio (Spearman rank correlations, 0.702; 95% confidence interval, 0.618-0.770; P < .001)., Conclusion: This study confirms that women with preeclampsia and chronic kidney disease without preeclampsia have elevated urine congophilia levels compared with healthy pregnant women. Nonpregnant women with lupus nephritis also have elevated urine congophilia levels compared with healthy control subjects. An elevated Congo Red stain retention may not be able to differentiate between these conditions; further research is required to explore the use of congophilia in clinical practice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Quantitative fetal fibronectin testing has demonstrated accuracy for prediction of spontaneous preterm birth in asymptomatic women with a history of preterm birth. Predictive accuracy in women with previous cervical surgery (a potentially different risk mechanism) is not known., Objective: We sought to compare the predictive accuracy of cervicovaginal fluid quantitative fetal fibronectin and cervical length testing in asymptomatic women with previous cervical surgery to that in women with 1 previous preterm birth., Study Design: We conducted a prospective blinded secondary analysis of a larger observational study of cervicovaginal fluid quantitative fetal fibronectin concentration in asymptomatic women measured with a Hologic 10Q system (Hologic, Marlborough, MA). Prediction of spontaneous preterm birth (<30, <34, and <37 weeks) with cervicovaginal fluid quantitative fetal fibronectin concentration in primiparous women who had undergone at least 1 invasive cervical procedure (n = 473) was compared with prediction in women who had previous spontaneous preterm birth, preterm prelabor rupture of membranes, or late miscarriage (n = 821). Relationship with cervical length was explored., Results: The rate of spontaneous preterm birth <34 weeks in the cervical surgery group was 3% compared with 9% in previous spontaneous preterm birth group. Receiver operating characteristic curves comparing quantitative fetal fibronectin for prediction at all 3 gestational end points were comparable between the cervical surgery and previous spontaneous preterm birth groups (34 weeks: area under the curve, 0.78 [95% confidence interval 0.64-0.93] vs 0.71 [95% confidence interval 0.64-0.78]; P = .39). Prediction of spontaneous preterm birth using cervical length compared with quantitative fetal fibronectin for prediction of preterm birth <34 weeks of gestation offered similar prediction (area under the curve, 0.88 [95% confidence interval 0.79-0.96] vs 0.77 [95% confidence interval 0.62-0.92], P = .12 in the cervical surgery group; and 0.77 [95% confidence interval 0.70-0.84] vs 0.74 [95% confidence interval 0.67-0.81], P = .32 in the previous spontaneous preterm birth group)., Conclusion: Prediction of spontaneous preterm birth using cervicovaginal fluid quantitative fetal fibronectin in asymptomatic women with cervical surgery is valid, and has comparative accuracy to that in women with a history of spontaneous preterm birth., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Study Question: Does ovarian stimulation affect perinatal outcomes of preterm birth (PTB) and low birth weight (LBW) following IVF treatment., Summary Answer: Despite no significant differences in the risks of PTB and LBW between stimulated and unstimulated IVF in the present study, the study cannot exclude the effect of ovarian stimulation on the perinatal outcomes following IVF., What Is Already Known: Pregnancies resulting from assisted reproductive treatments (ART) are associated with a higher risk of pregnancy complications compared to spontaneously conceived pregnancies attributed to the underlying infertility and the in vitro fertilization techniques. It is of interest to determine the effect size of ovarian stimulation use in achieving a live birth and whether ovarian stimulation that is routinely used in IVF, affects perinatal outcomes of birth weight and gestational age at delivery compared to unstimulated IVF., Study Design, Size, Duration: Anonymous data were obtained from the Human Fertilisation and Embryology Authority (HFEA), the statutory regulator of ART in the UK. The HFEA has collected data prospectively on all ART performed in the UK since 1991. Data from 1991 to 2011 comprising a total of 591 003 fresh IVF ± ICSI cycles involving 584 835 stimulated IVF cycles and 6168 unstimulated IVF cycles were analyzed., Participants/materials, Setting, Methods: Data on all women undergoing either stimulated or unstimulated fresh IVF ± ICSI cycles during the period from 1991 to 2011 were analyzed to compare live birth rates, singleton live birth rates, perinatal outcomes of PTB, early PTB (<32 weeks), LBW and very LBW (<1500 grams) among singleton live births. Adjusted logistic regression was performed for each perinatal outcome for confounding factors: female age, period of treatment, cause of infertility, number of previous IVF cycles and previous live birth., Main Results and the Role of Chance: Analysis of the large nationwide data demonstrated 3.5 times (95% confidence interval (CI): 3.1-3.9) as many unstimulated IVF cycles being required to achieve one live birth compared to stimulated IVF and 2.9 times (95% CI: 2.6-3.2) as many unstimulated IVF cycles being required to achieve one singleton live birth compared to stimulated IVF. There was no significant difference in the unadjusted odds for PTB (odds ratio (OR) 1.27, 95% CI: 0.80-2.00) and LBW (OR 1.48, 95% CI: 0.90-2.42) between stimulated and unstimulated IVF cycles. There was no significant difference in the risk of the adverse perinatal outcomes after adjusting for potential confounders; PTB (adjusted odds ratio (aOR) 1.43, 95% CI: 0.91-2.26) and LBW (aOR 1.58, 95% CI: 0.96-2.58)., Limitations, Reasons for Caution: Although the analysis was adjusted for a number of important confounders, the dataset had no information on smoking, body mass index (BMI) and the medical history of women during pregnancy to allow adjustment. Anonymized nature of the dataset did not make it permissible to analyse one cycle per woman. Given the smaller number of perinatal events with unstimulated IVF, a larger study is needed to investigate further., Wider Implications of the Findings: Analysis of this large dataset demonstrates that ovarian stimulation has a vital role in maximizing efficacy of IVF. Although there were no significant differences for PTB and LBW following stimulated compared to unstimulated IVF, the CIs were wide enough to include possible clinically important effects., Study Funding/competing Interests: No funding was obtained. There are no competing interests to declare., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Women with premature ovarian failure (POF) face many years of estrogen deficiency. One of the major consequences is bone loss. The optimal form of estrogen replacement is unknown and management is not evidence based. The 2 broad options are combined hormone replacement therapy (HRT) or the combined oral contraceptive pill (COCP)., Objectives: To compare the effects of HRT and COCP on bone density and turnover in women with spontaneous POF and to observe the effects of no treatment., Design: Two-year open randomized trial comparing HRT and COCP and nonrandomized observation of women declining treatment using the same protocol., Setting: London teaching hospital., Participants: A total of 59 women with spontaneous POF aged 18-44, 30 women elected to take treatment and were randomized, and 29 declined treatment., Intervention: Randomization was to HRT (Nuvelle) or COCP (Microgynon 30)., Main Outcome Measures: The primary outcome was change in lumbar spine bone mineral density. Changes in total hip and femoral neck bone density and bone turnover markers were also assessed., Results: A total of 36 women (61%) completed the trial (no treatment 52%; HRT 60%; COCP 80%). In comparison with COCP, treatment with HRT increased bone density at the lumbar spine at 2 years (+0.050 g/cm(2); 95% confidence interval 0.007-0.092; P = .025). Bone turnover markers showed similar reductions in the 2 treatment groups. In the no treatment group, bone density dropped at all sites and bone turnover markers remained relatively unchanged., Conclusions: The results suggest that HRT is superior to COCP in increasing bone density at the lumbar spine in women with spontaneous POF. The limitations of a small sample size and high drop-out rate mean that further research is required to confirm the findings. However, either treatment is clearly superior to no treatment.

Objective: To evaluate 47 biomarkers (selected from the current medical literature), in isolation or in combination with placental growth factor (PlGF), to determine the need for delivery within 14 days, in women presenting with suspected preterm preeclampsia., Methods: In a prospective, multicenter observational study, 47 biomarkers were measured in 423 women presenting with suspected preterm preeclampsia (in two prespecified groups: group 1 at less than 35 weeks of gestation and group 2 presenting between 35 0/7 and 36 6/7 weeks of gestation) to evaluate their ability to determine the primary endpoint: preeclampsia requiring delivery within 14 days. Using factor analysis and stepwise logistic regression, we sought one or more additional biomarkers for optimal determination of the primary endpoint., Results: In women presenting at less than 35 weeks of gestation (n=286), the best performing combination of PlGF, podocalyxin, endoglin, procalcitonin (receiver operating curve [ROC] area 0.90, 95% confidence interval [CI] 0.86-0.93) was not statistically better than PlGF alone (ROC 0.87, 95% CI 0.83-0.92; P=.43) for preeclampsia requiring delivery within 14 days. Two other single markers had test performance that was not significantly different to PlGF (soluble fms-like tyrosine kinase-1 [sFlt-1] ROC 0.83, 95% CI 0.78-0.88; endoglin ROC 0.83, 95% CI 0.79-0.88). Similar findings were found in women presenting between 35 0/7 and 36 6/7 weeks of gestation (n=137): ROC for PlGF alone 0.75 (95% CI 0.67-0.83); ROC for PlGF, cystatin, pregnancy-associated plasma protein A in combination 0.81 (95% CI 0.74-0.88; P=.40)., Conclusion: This study supports the growing body of evidence that a single angiogenesis-related biomarker (PlGF, sFlt-1, or endoglin) alone represents a useful diagnostic test for women presenting with suspected preterm preeclampsia.

Objective: To identify whether preterm surveillance clinics (PSCs) risk-stratify high-risk women accurately by comparing outcomes of those admitted to hospital on the basis of asymptomatic testing with those not admitted., Methods: We performed a subanalysis from a larger prospective cohort study on sonographic cervical length, quantitative fetal fibronectin (qfFN) and risk of spontaneous preterm birth. We identified 1130 asymptomatic singleton pregnancies at high risk of preterm birth, screened between 23 and 28 weeks of gestation at a PSC in a tertiary hospital in London, UK. Gestational age at delivery, the proportion of preterm births that delivered < 30 weeks and neonatal outcomes were compared between women admitted electively when asymptomatic as a consequence of screening-test results and those who were not routinely admitted., Results: In total, 66 (6%) women attending the PSC were admitted to hospital following asymptomatic screening (inpatient group). The mean gestational age at delivery for those not admitted electively (outpatient group) was at term and was significantly higher than that of those admitted from PSC (38.4 vs 31.2 weeks; P < 0.0001). Preterm birth < 30 weeks' gestation was rare in the outpatient group relative to those admitted (1.32% vs 36.4%; P < 0.0001). Neonatal mortality was 0.188% in the outpatient group compared with 4.55% in those admitted electively (P < 0.0001). The incidence of other complications such as neonatal death, 5-min Apgar score < 7, special care baby unit/neonatal intensive care unit admission, respiratory distress syndrome, intraventricular hemorrhage and low birth weight were significantly lower in those managed as outpatients than in those admitted electively., Conclusion: PSCs measuring cervical length and qfFN accurately triage asymptomatic high-risk pregnant women, enabling those at highest risk of adverse outcome to be identified for elective admission to hospital and appropriate management. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: The objective of this study is to investigate the effects of the UK Pregnancies Better Eating and Activity Trial (UPBEAT) behavioral intervention on dietary patterns in obese pregnant women., Methods: Dietary patterns were derived from Food Frequency Questionnaires using principal component analysis in 183 UPBEAT pilot study participants., Results: Two unhealthy dietary patterns, processed and traditional, predominantly characterized by foods high in sugar and fat, improved [processed -0.54 (-0.92 to -0.16), P = 0.006 and traditional -0.83 (-1.20 to -0.45), P < 0.001] following the intervention, while a cultural pattern that was found to be associated with the Black African/Caribbean participants did not change [-0.10 (-0.46 to 0.26), P = 0.589]., Conclusion: Unhealthy dietary patterns are evident in obese pregnant women. The UPBEAT intervention was effective in improving maternal dietary patterns; however, obese pregnant women from minority ethnic groups may be less receptive to intervention.

Background: The success rate of in-vitro fertilisation (IVF) remains low and many women undergo multiple treatment cycles. A previous meta-analysis suggested hysteroscopy could improve outcomes in women who have had recurrent implantation failure; however, studies were of poor quality and a definitive randomised trial was needed. In the TROPHY trial we aimed to assess whether hysteroscopy improves the livebirth rate following IVF treatment in women with recurrent failure of implantation., Methods: We did a multicentre, randomised controlled trial in eight hospitals in the UK, Belgium, Italy, and the Czech Republic. We recruited women younger than 38 years who had normal ultrasound of the uterine cavity and history of two to four unsuccessful IVF cycles. We used an independent web-based trial management system to randomly assign (1:1) women to receive outpatient hysteroscopy (hysteroscopy group) or no hysteroscopy (control group) in the month before starting a treatment cycle of IVF (with or without intracytoplasmic sperm injection). A computer-based algorithm minimised for key prognostic variables: age, body-mass index, basal follicle-stimulating hormone concentration, and the number of previous failed IVF cycles. The order of group assignment was masked to the researchers at the time of recruitment and randomisation. Embryologists involved in the embryo transfer were masked to group allocation, but physicians doing the procedure knew of group assignment and had hysteroscopy findings accessible. Participants were not masked to their group assignment. The primary outcome was the livebirth rate (proportion of women who had a live baby beyond 24 weeks of gestation) in the intention-to-treat population. The trial was registered with the ISRCTN Registry, ISRCTN35859078., Findings: Between Jan 1, 2010, and Dec 31, 2013, we randomly assigned 350 women to the hysteroscopy group and 352 women to the control group. 102 (29%) of women in the hysteroscopy group had a livebirth after IVF compared with 102 (29%) women in the control group (risk ratio 1·0, 95% CI 0·79-1·25; p=0·96). No hysteroscopy-related adverse events were reported., Interpretation: Outpatient hysteroscopy before IVF in women with a normal ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve the livebirth rate. Further research into the effectiveness of surgical correction of specific uterine cavity abnormalities before IVF is warranted., Funding: European Society of Human Reproduction and Embryology, European Society for Gynaecological Endoscopy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Objectives: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted., Design and Setting: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites)., Participants and Interventions: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks)., Main Outcome Measures: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use., Methods: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth., Results: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341., Conclusions: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM., Limitations: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle., Future Work: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM., Trial Registration: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Unlabelled: A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice., Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP., (© 2015 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Women with chronic kidney disease (CKD) and chronic hypertension (CHT) frequently develop superimposed pre-eclampsia, but distinction from pre-existing disease is challenging. Plasma placental growth factor (PlGF), B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), and serum relaxin concentrations were quantified in a longitudinal prospective cohort of 121 women with CKD: 44 with chronic hypertension, and 79 healthy controls. Biomarker concentrations were compared with 32 women with pre-eclampsia without pre-existing disease. Test performance was evaluated for diagnosis of superimposed pre-eclampsia requiring delivery within 14 days of sampling. PlGF was evaluated as a promising marker in a validation cohort of women with suspected pre-eclampsia (29 with CKD; 94 with chronic hypertension; 29 with superimposed pre-eclampsia requiring delivery within 14 days) and compared with women without pre-existing disease (290 with no pre-eclampsia and 176 with pre-eclampsia requiring delivery within 14 days). From 20 and up to 42 weeks of gestation, lower maternal PlGF concentrations had high diagnostic accuracy for superimposed pre-eclampsia requiring delivery within 14 days (receiver operator characteristic 0.85) and confirmed in the validation cohort. The other plasma and serum biomarkers were not discriminatory. Thus, plasma PlGF concentrations could potentially help guide clinical decision making regarding admission and delivery for superimposed pre-eclampsia., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the optimal vital sign predictor of adverse maternal outcomes in women with hypovolemic shock secondary to obstetric hemorrhage and to develop thresholds for referral/intensive monitoring and need for urgent intervention to inform a vital sign alert device for low-resource settings., Study Design: We conducted secondary analyses of a dataset of pregnant/postpartum women with hypovolemic shock in low-resource settings (n = 958). Using receiver-operating curve analysis, we evaluated the predictive ability of pulse, systolic blood pressure, diastolic blood pressure, shock index, mean arterial pressure, and pulse pressure for three adverse maternal outcomes: (1) death, (2) severe maternal outcome (death or severe end organ dysfunction morbidity); and (3) a combined severe maternal and critical interventions outcome comprising death, severe end organ dysfunction morbidity, intensive care admission, blood transfusion ≥ 5 units, or emergency hysterectomy. Two threshold parameters with optimal rule-in and rule-out characteristics were selected based on sensitivities, specificities, and positive and negative predictive values., Results: Shock index was consistently among the top two predictors across adverse maternal outcomes. Its discriminatory ability was significantly better than pulse and pulse pressure for maternal death (p<0.05 and p<0.01, respectively), diastolic blood pressure and pulse pressure for severe maternal outcome (p<0.01), and systolic and diastolic blood pressure, mean arterial pressure and pulse pressure for severe maternal outcome and critical interventions (p<0.01). A shock index threshold of ≥ 0.9 maintained high sensitivity (100.0) with clinical practicality, ≥ 1.4 balanced specificity (range 70.0-74.8) with negative predictive value (range 93.2-99.2), and ≥ 1.7 further improved specificity (range 80.7-90.8) without compromising negative predictive value (range 88.8-98.5)., Conclusions: For women with hypovolemic shock from obstetric hemorrhage, shock index was consistently a strong predictor of all adverse outcomes. In lower-level facilities in low resource settings, we recommend a shock index threshold of ≥ 0.9 indicating need for referral, ≥ 1.4 indicating urgent need for intervention in tertiary facilities and ≥ 1.7 indicating high chance of adverse outcome. The vital sign alert device incorporated values 0.9 and 1.7; however, all thresholds will be prospectively validated and clinical pathways for action appropriate to setting established prior to clinical implementation.

Objective: To compare quantitative fetal fibronectin measurement from 18 to 21 weeks of gestation to measurement at 22-27 weeks of gestation for the prediction of spontaneous preterm birth., Methods: In a prospective cohort study, we studied the accuracy of cervicovaginal fluid quantitative fetal fibronectin concentrations measured between 18 0/7 weeks of gestation and 21 6/7 weeks of gestation in high-risk asymptomatic women to predict spontaneous preterm birth before 34 weeks of gestation. Predefined fibronectin thresholds were 10 or greater, 50 or greater, and 200 ng/mL or greater. Diagnostic accuracy of the early test (n=898) was compared with the standard test performed between 22 0/7 and 27 6/7 weeks of gestation (n=691) in the same cohort. Subgroup analysis was performed according to cervical length measurement., Results: Of 898 women, 8.7% delivered spontaneously before 34 weeks of gestation. Only 3.8% of the women with concentrations less than 10 ng/mL (65% of test results) delivered before 34 weeks of gestation. A concentration threshold of 10 ng/mL measured at 18 and 22 weeks of gestation had comparably high sensitivity (early 0.71, 95% confidence interval 0.60-0.81; standard 0.76, 0.63-0.87) and negative predictive value (early 0.96, 0.94-0.98; standard 0.97, 0.95-0.99) for delivery before 34 weeks of gestation. Specificity was also comparable (early 0.69, 0.65-0.72; standard 0.70, 0.66-0.74). A threshold of 200 ng/mL had high specificity (early 0.96, 0.94-0.98; standard 0.96, 0.94-0.97) with lower sensitivity (early 0.26, 0.17-0.37; standard 0.35, 0.22-0.49). Consideration of cervical length strengthened prediction., Conclusion: Quantitative cervicovaginal fetal fibronectin measured from 18 to 21 weeks of gestation has similar predictive value as measurement at 22-27 weeks of gestation for prediction of spontaneous preterm birth. Low fibronectin concentrations are associated with spontaneous preterm birthrates approaching population background levels.

Objective: To develop a reliable and validated tool for prediction of spontaneous preterm birth (sPTB) in symptomatic women that incorporates quantitative measurements of fetal fibronectin (qfFN) and other relevant risk factors., Methods: Data were analyzed that had been collected prospectively from 382 women who presented at an emergency assessment unit between 22 + 0 and 35 + 6 weeks' gestation with symptoms of preterm labor. Clinicians were blinded to qfFN although they were aware of qualitative fFN results. Parametric survival models for sPTB, with time-updated covariates, were developed for combinations of predictors and the best was selected using the Akaike and Bayesian information criteria. The model was developed on the first 190 consecutive women and validated on the subsequent 192. The estimated probability of delivery before 30, 34 or 37 weeks' gestation and within 2 or 4 weeks of testing was calculated for each patient and was compared to actual event rates. Predictive statistics were calculated to compare training and validation sets., Results: The final model that was selected used qfFN and previous sPTB/preterm prelabor rupture of membranes (PPROM) as predictors. Predictive statistics were similar for training and validation sets and there was good agreement between expected and observed sPTB for all outcomes. Areas under the receiver-operating characteristics curves ranged from 0.77 to 0.88, indicating accurate prediction across all five delivery outcomes., Conclusions: sPTB in symptomatic women can be predicted accurately using a model combining qfFN and previous sPTB/PPROM. Clinicians can use this model, which has been incorporated into an App (QUiPP), to determine accurately a woman's risk of sPTB and potentially tailor management decisions appropriately., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To develop a predictive tool for spontaneous preterm birth (sPTB) in asymptomatic high-risk women that includes quantification of fetal fibronectin (fFN) along with cervical length (CL) measurement and other clinical factors., Methods: Data were analyzed that had been collected prospectively from 1249 women at high risk for sPTB attending preterm surveillance clinics. Clinicians were blinded to quantitative measurements of fFN (qfFN), although they were aware of qualitative fFN results. Parametric survival models for sPTB, with time-updated covariates, were developed and the best was selected using the Akaike and Bayesian information criteria. The model was developed on the first 624 consecutive women and validated on the subsequent 625. Fractional polynomials were used to accommodate possible non-linear effects of qfFN and CL. The estimated probability of delivery before 30, 34 or 37 weeks' gestation and within 2 or 4 weeks of testing was calculated for each patient and analyzed as a predictive test for the actual occurrence of each event. Predictive statistics were calculated to compare training and validation sets., Results: The final model that was selected used a log-normal survival curve with CL, √qfFN and previous sPTB/preterm prelabor rupture of membranes as predictors. Predictive statistics were similar for training and validation sets. Areas under the receiver-operating characteristics curves ranged from 0.77 to 0.99, indicating accurate prediction across all five delivery outcomes., Conclusions: sPTB in high-risk asymptomatic women can be predicted accurately using a model combining qfFN and CL, which supersedes the single-threshold fFN test, demographic information and obstetric history. This algorithm has been incorporated into an App (QUiPP) for widespread use., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain., Methods: We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation., Results: A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events., Conclusions: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).

Background: Behavioural interventions might improve clinical outcomes in pregnant women who are obese. We aimed to investigate whether a complex intervention addressing diet and physical activity could reduce the incidence of gestational diabetes and large-for-gestational-age infants., Methods: The UK Pregnancies Better Eating and Activity Trial (UPBEAT) is a randomised controlled trial done at antenatal clinics in eight hospitals in multi-ethnic, inner-city locations in the UK. We recruited pregnant women (15-18 weeks plus 6 days of gestation) older than 16 years who were obese (BMI ≥30 kg/m(2)). We randomly assigned participants to either a behavioural intervention or standard antenatal care with an internet-based, computer-generated, randomisation procedure, minimising by age, ethnic origin, centre, BMI, and parity. The intervention was delivered once a week through eight health trainer-led sessions. Primary outcomes were gestational diabetes (diagnosed with an oral glucose tolerance test and by criteria from the International Association of Diabetes in Pregnancy Study Groups) and large-for-gestational-age infants (≥90th customised birthweight centile). Analysis was by intention to treat. This trial is registered with Current Controlled Trials, ISCRTN89971375. Recruitment and pregnancy outcomes are complete but childhood follow-up is ongoing., Findings: Between March 31, 2009, and June 2, 2014, we assessed 8820 women for eligibility and recruited 1555, with a mean BMI of 36·3 kg/m(2) (SD 4·8). 772 were randomly assigned to standard antenatal care and 783 were allocated the behavioural intervention, of which 651 and 629 women, respectively, completed an oral glucose tolerance test. Gestational diabetes was reported in 172 (26%) women in the standard care group compared with 160 (25%) in the intervention group (risk ratio 0·96, 95% CI 0·79-1·16; p=0·68). 61 (8%) of 751 babies in the standard care group were large for gestational age compared with 71 (9%) of 761 in the intervention group (1·15, 0·83-1·59; p=0·40). Thus, the primary outcomes did not differ between groups, despite improvements in some maternal secondary outcomes in the intervention group, including reduced dietary glycaemic load, gestational weight gain, and maternal sum-of-skinfold thicknesses, and increased physical activity. Adverse events included neonatal death (two in the standard care group and three in the intervention group) and fetal death in utero (ten in the standard care group and six in the intervention group). No maternal deaths were reported. Incidence of miscarriage (2% in the standard care group vs 2% in the intervention group), major obstetric haemorrhage (1% vs 3%), and small-for-gestational-age infants (≤5th customised birthweight centile; 6% vs 5%) did not differ between groups., Interpretation: A behavioural intervention addressing diet and physical activity in women with obesity during pregnancy is not adequate to prevent gestational diabetes, or to reduce the incidence of large-for-gestational-age infants., Funding: National Institute for Health Research, Guys and St Thomas' Charity, Chief Scientist Office Scotland, Tommy's Charity., (Copyright © 2015 Poston et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the diagnostic accuracy of placental growth factor (PlGF) and ultrasound parameters to predict delivery of a small-for-gestational-age (SGA) infant in women presenting with reduced symphysis-fundus height (SFH)., Methods: This was a multicenter prospective observational study recruiting 601 women with a singleton pregnancy and reduced SFH between 24 and 37 weeks' gestation across 11 sites in the UK and Canada. Plasma PlGF concentration < 5(th) centile, estimated fetal weight (EFW) < 10(th) centile, umbilical artery Doppler pulsatility index > 95(th) centile and oligohydramnios (amniotic fluid index < 5 cm) were compared as predictors for a SGA infant < 3(rd) customized birth-weight centile and adverse perinatal outcome. Test performance statistics were calculated for all parameters in isolation and in combination., Results: Of the 601 women recruited, 592 were analyzed. For predicting delivery of SGA < 3(rd) centile (n = 78), EFW < 10(th) centile had 58% sensitivity (95% CI, 46-69%) and 93% negative predictive value (NPV) (95% CI, 90-95%), PlGF had 37% sensitivity (95% CI, 27-49%) and 90% NPV (95% CI, 87-93%); in combination, PlGF and EFW < 10(th) centile had 69% sensitivity (95% CI, 55-81%) and 93% NPV (95% CI, 89-96%). The equivalent receiver-operating characteristics (ROC) curve areas were 0.79 (95% CI, 0.74-0.84) for EFW < 10(th) centile, 0.70 (95% CI, 0.63-0.77) for low PlGF and 0.82 (95% CI, 0.77-0.86) in combination., Conclusions: For women presenting with reduced SFH, ultrasound parameters had modest test performance for predicting delivery of SGA < 3(rd) centile. PlGF performed no better than EFW < 10(th) centile in determining delivery of a SGA infant., (© 2015 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the international society of ultrasound in obstetrics and gynecology.)

Background: Low health literacy is associated with poorer health and higher mortality. Complex health materials are a barrier to health., Aim: To assess the literacy and numeracy skills required to understand and use commonly used English health information materials, and to describe population skills in relation to these., Design and Setting: An English observational study comparing health materials with national working-age population skills., Method: Health materials were sampled using a health literacy framework. Competency thresholds to understand and use the materials were identified. The proportion of the population above and below these thresholds, and the sociodemographic variables associated with a greater risk of being below the thresholds, were described., Results: Sixty-four health materials were sampled. Two competency thresholds were identified: text (literacy) only, and text + numeracy; 2515/5795 participants (43%) were below the text-only threshold, while 2905/4767 (61%) were below the text + numeracy threshold. Univariable analyses of social determinants of health showed that those groups more at risk of socioeconomic deprivation had higher odds of being below the health literacy competency threshold than those at lower risk of deprivation. Multivariable analysis resulted in some variables becoming non-significant or reduced in effect., Conclusion: Levels of low health literacy mirror those found in other industrialised countries, with a mismatch between the complexity of health materials and the skills of the English adult working-age population. Those most in need of health information have the least access to it. Efficacious strategies are building population skills, improving health professionals' communication, and improving written health information., (© British Journal of General Practice 2015.)

Study Question: Is there a relation between the number of oocytes retrieved following ovarian stimulation and obstetric outcomes of preterm birth (PTB) and low birthweight (LBW) following IVF treatment?, Summary Answer: There is an increased risk of PTB (<37 weeks gestation) and LBW (<2500 g) following IVF in women with a high number (>20) of oocytes retrieved., What Is Known Already: Pregnancies resulting from assisted reproductive treatments (ART) are associated with a higher risk of pregnancy complications compared with spontaneously conceived pregnancies. Whether ovarian ageing in women with poor ovarian response is associated with an increased risk of adverse obstetric outcomes is debated. It is also unclear if an excessive response and high egg numbers following ovarian stimulation have an association with adverse obstetric outcomes., Study Design, Size, Duration: Observational study using anonymized data on all IVF cycles performed in the UK from August 1991 to June 2008. Data from 402 185 IVF cycles and 65 868 singleton live birth outcomes were analysed., Participants/materials, Setting, Methods: Data on all women undergoing a stimulated fresh IVF cycle with at least one oocyte retrieved between 1991 and June 2008 were analysed for birth outcomes. Logistic regression analysis of the association between ovarian response (quantified as number of oocytes retrieved) and outcomes of PTB and LBW was performed., Main Results and the Role of Chance: There was a significantly higher risk of adverse obstetric outcomes of PTB and LBW among women with an excessive response (>20 oocytes) compared with women with a normal response (10-15 oocytes): adjusted odds ratio (OR) 1.15, 95% confidence interval (CI) 1.03-1.28 for PTB, adjusted OR 1.17, 95% CI 1.05-1.30 for LBW, respectively. There was no increased risk of the adverse outcomes among women with a poor ovarian response (≤3 oocytes) compared with women with a normal response: adjusted OR 0.88, 95% CI 0.76-1.01 for PTB, adjusted OR 0.92, 95% CI 0.79-1.06 for LBW, respectively., Limitations, Reasons for Caution: Although the analysis was adjusted for a number of potential confounders, the dataset had no information on other important confounders such as smoking, BMI and the medical history of women during pregnancy. Furthermore, the dataset did not allow specific identification of women with PCOS and its anonymized nature did not make it permissible to analyse one cycle per woman., Wider Implications of the Findings: Analysis of this large dataset suggests that a high oocyte number (>20) following IVF is associated with a higher risk of PTB and LBW. These findings lead to speculation whether ovarian dysfunction and/or an altered endometrial milieu resulting from supraphysiological steroid levels underlie the unfavourable outcomes and warrant further research. Ovarian stimulation regimens should optimize the number of oocytes retrieved to avoid the risk of adverse outcomes associated with very high numbers of oocytes., Study Funding/competing Interests: No funding was obtained. There are no competing interests to declare., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A systematic review and meta-analysis of observational studies were conducted to quantify the association between sickle cell disease in pregnancy and adverse maternal and perinatal outcomes. Data sources (Medline, Embase, Maternity and Infant care, Cochrane, Web of Science, Popline) were searched for publications to June 2014. Eligibility criteria included observational studies reporting maternal and perinatal health outcomes in pregnant women with sickle cell disease against a comparative group of pregnant women without sickle cell disease. Twenty-one studies (including 26,349 women with sickle cell disease; 26,151,746 women without sickle cell disease) were eligible for inclusion. Pregnancies in women with HbSS genotype, compared with women without sickle cell disease, were at increased risk of maternal mortality (relative risk [RR], 5.98; 95% confidence interval [CI], 1.94-18.44), preeclampsia (RR, 2.43; 95% CI, 1.75-3.39), stillbirth (RR, 3.94; 95% CI, 2.60-5.96), preterm delivery (RR, 2.21; 95% CI, 1.47-3.31), and small for gestational age infants (RR, 3.72; 95% CI, 2.32-5.98). Meta-regression demonstrated that genotype (HbSS vs HbSC), low gross national income, and high study quality were associated with increased RRs. Despite advances in the management of sickle cell disease, obstetrics, and neonatal medicine, pregnancies complicated by the disease remain associated with increased risk of adverse maternal and perinatal outcomes., (© 2015 by The American Society of Hematology.)

Lack of reproducibility is an ongoing problem in some areas of the biomedical sciences. Poor experimental design and a failure to engage with experienced statisticians at key stages in the design and analysis of experiments are two factors that contribute to this problem. The RIPOSTE (Reducing IrreProducibility in labOratory STudiEs) framework has been developed to support early and regular discussions between scientists and statisticians in order to improve the design, conduct and analysis of laboratory studies and, therefore, to reduce irreproducibility. This framework is intended for use during the early stages of a research project, when specific questions or hypotheses are proposed. The essential points within the framework are explained and illustrated using three examples (a medical equipment test, a macrophage study and a gene expression study). Sound study design minimises the possibility of bias being introduced into experiments and leads to higher quality research with more reproducible results.

Background: Controversy surrounds the effectiveness of dietary guidelines for cardiovascular disease (CVD) prevention in healthy middle-aged and older men and women., Objective: The objective was to compare effects on vascular and lipid CVD risk factors of following the United Kingdom dietary guidelines with a traditional British diet (control)., Design: With the use of a parallel-designed randomized controlled trial in 165 healthy nonsmoking men and women (aged 40-70 y), we measured ambulatory blood pressure (BP) on 5 occasions, vascular function, and CVD risk factors at baseline and during 12 wk after random assignment to treatment. The primary outcomes were differences between treatments in daytime ambulatory systolic BP, flow-mediated dilation, and total cholesterol/HDL cholesterol. Secondary outcomes were differences between treatment in carotid-to-femoral pulse wave velocity, high-sensitivity C-reactive protein, and a measure of insulin sensitivity (Revised Quantitative Insulin Sensitivity Check Index)., Results: Data were available on 162 participants, and adherence to the dietary advice was confirmed from dietary records and biomarkers of compliance. In the dietary guidelines group (n = 80) compared with control (n = 82), daytime systolic BP was 4.2 mm Hg (95% CI: 1.7, 6.6 mm Hg; P < 0.001) lower, the treatment effect on flow-mediated dilation [-0.62% (95% CI: -1.48%, 0.24%)] was not significant, the total cholesterol:HDL cholesterol ratio was 0.13 (95% CI: 0, 0.26; P = 0.044) lower, pulse wave velocity was 0.29 m/s (95% CI: 0.07, 0.52 m/s; P = 0.011) lower, high-sensitivity C-reactive protein was 36% (95% CI: 7%, 48%; P = 0.017) lower, the treatment effect on the Revised Quantitative Insulin Sensitivity Check Index [2% (95% CI: -2%, 5%)] was not significant, and body weight was 1.9 kg (95% CI: 1.3, 2.5 kg; P < 0.001) lower. Causal mediated effects analysis based on urinary sodium excretion indicated that sodium reduction explained 2.4 mm Hg (95% CI: 1.0, 3.9 mm Hg) of the fall in blood pressure., Conclusion: Selecting a diet consistent with current dietary guidelines lowers BP and lipids, which would be expected to reduce the risk of CVD by one-third in healthy middle-aged and older men and women. This study is registered at www.isrctn.com as 92382106., (© 2015 American Society for Nutrition.)

Objective: To evaluate the diagnostic accuracy of cervicovaginal fluid quantitative fetal fibronectin, measured by a bedside analyzer, to predict spontaneous preterm birth before 34 weeks of gestation., Methods: We conducted a prospective masked observational cohort study of cervicovaginal fluid quantitative fetal fibronectin concentration in asymptomatic women at high risk of spontaneous preterm birth (n=1,448; 22-27 6/7 weeks of gestation) measured using a rapid bedside analyzer. The routine qualitative result (positive-negative) was made available to clinicians at the time of testing, but the quantitative result remained blinded until after delivery., Results: Spontaneous preterm birth (less than 34 weeks of gestation) increased from 2.7%, 11.0%, 14.9%, 33.9%, and 47.6% with increasing concentration of fetal fibronectin (less than 10, 10-49, 50-199, 200-499, and 500 ng/mL or greater, respectively). A threshold of 200 ng/mL had a positive predictive value of 37.7 (95% confidence interval [CI] 26.9-49.4) with specificity 96% (95% CI 95.3-97.3). Women with a fetal fibronectin concentration of less than 10 ng/mL had a very low risk of spontaneous preterm birth at less than 34 weeks of gestation (2.7%), no higher than the background spontaneous preterm birth rate of the general hospital population (3.3%). The quantitative fetal fibronectin test predicted birth at less than 34 weeks of gestation with an area under the curve (AUC) of 0.78 (95% CI 0.73-0.84) compared with the qualitative test AUC 0.68 (95% CI 0.63-0.73). Quantitative fetal fibronectin discriminated risk of spontaneous preterm birth at less than 34 weeks of gestation among women with a short cervix (less than 25 mm); 9.5% delivered prematurely less than 10 ng/mL compared with 55.1% greater than 200 ng/mL (P<.001)., Discussion: Alternative risk thresholds (less than 10 ng/mL and greater than 200 ng/mL) improve accuracy when using quantitative fetal fibronectin measurements to define risk of spontaneous preterm birth. This is particularly relevant for asymptomatic women with a short cervix., Level of Evidence: II.

Objective: To determine the subsequent need for cerclage and pregnancy outcome, in women with a prior ultrasound-indicated cerclage., Study Design: Analysis of a prospectively collected database from November 2010 to July 2014 from 15 Preterm Surveillance clinics across the UK was performed. Women with an index and previous singleton pregnancy with an ultrasound-indicated cerclage were eligible for inclusion (n=55). Previous ultrasound-indicated cerclage was defined as cerclage inserted prior to 24 weeks' for cervical length <25 mm as detected by transvaginal ultrasound. Women were managed in their subsequent pregnancy with either history-indicated cerclage, transvaginal ultrasound surveillance of cervical length with cerclage if <25 mm or transabdominal cerclage at the discretion of the physician. Exact logistic regression was used to estimate the odds ratio on the chance of delivery before 34 weeks'. Adjustments were made for major risk factors for prematurity: previous spontaneous preterm birth, previous late miscarriage (16+0 to 23+6 weeks') and previous cervical surgery; both individually and in combination., Results: Of the 55 eligible women, 23 underwent history-indicated cerclage, 23 underwent transvaginal ultrasound cervical length surveillance and 8 underwent abdominal cerclage in the index pregnancy. Of those that had ultrasound surveillance, 13 (57%) did not require cerclage and all delivered after 34 weeks'. Of those that had a history-indicated cerclage, six delivered before 34 weeks'. Therefore, women that received a history-indicated cerclage had greater risk of preterm birth compared to women that underwent ultrasound surveillance with cerclage insertion only if cervical shortening was detected (OR 0.09 95% CI 0.00-0.74, p=0.02). Adjustments for risk factors for preterm birth did not significantly affect this risk., Conclusion: In women with prior ultrasound-indicated cerclage, who undergo cervical surveillance in the next pregnancy, the majority will not require intervention for a short cervix. Those women receiving a history-indicated vaginal cerclage were more likely to deliver preterm; this cannot be explained by their risk status. All women receiving an abdominal elective cerclage had good outcomes. Ultrasound surveillance is appropriate in women with a prior ultrasound-indicated cerclage who do not require an abdominal cerclage., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The antiphospholipid syndrome (APS) is the association of thrombosis and recurrent pregnancy loss and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). Previous studies of microparticles in patients with APS/aPL have mainly been small and findings, contradictory., Objectives: To quantify endothelial and platelet microparticle levels in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome (PAPS)., Patients/methods: We measured endothelial and platelet microparticle levels by flow cytometry in 66 aPL/PAPS patients and 18 healthy controls., Results: Levels of circulating platelet (CD41 and CD61) and endothelial microparticles (CD51 and CD105) were significantly increased in patients with PAPS and aPL compared to healthy controls. There were correlations between platelet and endothelial microparticles levels in all patients with aPL., Conclusions: Platelet and endothelial microparticles are increased in all patient groups within this cohort of patients aPL. Whether they may have a role in the pathogenesis of APS merits further study., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To assess a full dilatation cesarean delivery simulator and to establish expert consensus on the most effective techniques for safe delivery., Methods: Three delivery scenarios with increasing degrees of difficulty were tested. Face and content validity were assessed using visual analog scale (VAS) scores on how realistic the simulator was and how useful it would be for training, respectively. Construct validity was assessed by comparing success at delivery and time taken between senior doctors and junior doctors. Expert opinion was sought through a questionnaire., Results: The training scenarios were undertaken by 30 doctors working in the specialty of obstetrics and gynecology. The number of participants able to deliver and the perceived difficulty they experienced correlated with the difficulty level of the three scenarios (success: scenario 1, 100% [n=30]; scenario 2, 90% [n=27]; and scenario 3, 62% [n=16] P<.05; mean VAS: scenario 1, 29/100; scenario 2, 42/100; and scenario 3, 88/100; P<.001). Average time to delivery for each scenario was 45 seconds, 43 seconds, and 109 seconds, respectively (P<.001). Overall, 87% found the simulator to be realistic (median VAS 58/100, interquartile range 40-74) and 93% thought it would be useful as a training device (median VAS 80/100, interquartile range 55-97). Questionnaires were received from 47 consultants with an average of 18 years of experience. High uterine incision and assistance to push the fetal head up transvaginally were the only two techniques reported by more than half of the respondents., Conclusion: This full dilatation cesarean delivery simulator has been validated as a training device; we believe it should be used to develop a consensus for accepted techniques.

Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Deficiencies of specific micronutrient antioxidant activities associated with copper, selenium, zinc, and manganese have previously been linked to preeclampsia at the time of disease. Our aims were to investigate whether maternal plasma micronutrient concentrations and related antioxidant enzyme activities are altered before preeclampsia onset and to examine the dependence on genetic variations in these antioxidant enzymes. Predisease plasma samples (15±1 weeks׳ gestation) were obtained from women enrolled in the international Screening for Pregnancy Endpoints (SCOPE) study who subsequently developed preeclampsia (n=244) and from age- and BMI-matched normotensive controls (n=472). Micronutrient concentrations were measured by inductively coupled plasma mass spectrometry; associated antioxidant enzyme activities, selenoprotein-P, ceruloplasmin concentration and activity, antioxidant capacity, and markers of oxidative stress were measured by colorimetric assays. Sixty-four tag-single-nucleotide polymorphisms (SNPs) within genes encoding the antioxidant enzymes and selenoprotein-P were genotyped using allele-specific competitive PCR. Plasma copper and ceruloplasmin concentrations were modestly but significantly elevated in women who subsequently developed preeclampsia (both P<0.001) compared to controls (median (IQR), copper, 1957.4 (1787, 2177.5) vs 1850.0 (1663.5, 2051.5) µg/L; ceruloplasmin, 2.5 (1.4, 3.2) vs 2.2 (1.2, 3.0) µg/ml). There were no differences in other micronutrients or enzymes between groups. No relationship was observed between genotype for SNPs and antioxidant enzyme activity. This analysis of a prospective cohort study reports maternal micronutrient concentrations in combination with associated antioxidant enzymes and SNPs in their encoding genes in women at 15 weeks׳ gestation that subsequently developed preeclampsia. The modest elevation in copper may contribute to oxidative stress, later in pregnancy, in those women that go on to develop preeclampsia. The lack of evidence to support the hypothesis that functional SNPs influence antioxidant enzyme activity in pregnant women argues against a role for these genes in the etiology of preeclampsia., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to determine the effect of sexual intercourse on the accuracy of quantitative fetal fibronectin (qfFN) in the prediction of spontaneous preterm birth (sPTB) in asymptomatic high-risk women., Study Design: This was a prospective masked predefined subanalysis of a larger study of cervicovaginal fluid qfFN concentration in high-risk women asymptomatic of preterm labor. Women who had sexual intercourse within 48 hours of qfFN testing (n = 61; 18(+0)-34(+6) weeks' gestation) were compared with controls from the same database without a history of pretest sexual intercourse, matched according to gestational age at testing and delivery, risk factor for sPTB, and ultrasonographic cervical length measurement., Results: The median concentration of qfFN in women who had sexual intercourse within 48 hours of testing was 53 ng/mL (quartiles 6, 189), compared with 5 ng/mL (quartiles 2, 12) in the control group. The average qfFN concentration was 6.36 (95% confidence interval [CI], 3.43-11.8) times higher in the sexual intercourse group compared with controls (P < .0001). The false-positive rate was 56% (27 of 50) compared with 6% (3 of 52) in the control group (risk difference, 48%; 95% CI, 33-63; P < .001). The false-negative rate was 45% (5 of 11) vs 89% (8 of 9) in the control group (risk difference, -43%; 95% CI, -79 to -8; P = .043)., Conclusion: Sexual intercourse within 48 hours of testing is associated with increased levels of fetal fibronectin in vaginal secretions and an increased rate of false-positive results in the prediction of sPTB in asymptomatic women., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Study Question: Which variables at 15 and 20 weeks' gestation, particularly those amenable to modification before pregnancy, are associated with a subsequent uncomplicated pregnancy?, Summary Answer: Normalising body mass index, increasing fruit intake before pregnancy, reducing blood pressure, stopping misuse of drugs, and being in paid employment are all associated with subsequent uncomplicated pregnancy outcomes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: Anecdotal reports suggest that clopidogrel may prevent migraine attacks. We undertook a pilot randomised trial., Method: We randomised consecutive migraineurs with four to 15 headache days per 28-day month to receive clopidogrel 75 mg or placebo daily for three months. Headache was primarily assessed with a headache diary., Results: There were no statistically significant treatment effects. The number of headache days fell by 1.9 on clopidogrel and 1.6 on placebo (adjusted difference 0.02, CI -2.07 to 2.12). Headache severity rose by 0.14 points (out of 10) on clopidogrel, and fell by 0.63 on placebo; treatment effect 0.7 points (CI -0.11 to 1.57). The main treatment effect did not depend on the presence or absence of migraine with aura at baseline, a patent foramen ovale (PFO) or atrial septal aneurysm., Discussion: The evidence is inconclusive, but a multicentre trial would be feasible recruiting from primary care., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Aim: To examine the prediction of gestational diabetes in obese women using routine clinical measures and measurement of biomarkers related to insulin resistance in the early second trimester., Methods: A total of 117 obese pregnant women participating in a pilot trial of a complex intervention of dietary advice and physical activity were studied. Blood samples were obtained at recruitment (15⁺⁰-17⁺⁶ weeks' gestation) and demographic, clinical history and anthropometric measures recorded. The biomarkers analysed were plasma lipids (HDL cholesterol, LDL cholesterol, triglycerides), high-sensitivity C-reactive protein, alanine transaminase, aspartate transaminase, ferritin, fructosamine, insulin, adiponectin, tissue plasminogen activator, interleukin-6, visfatin and leptin. Univariate and logistic regression analyses were performed to determine independent predictors and area under the receiver-operating curve was calculated for the model., Results: Of the 106 participants included in the analysis, 29 (27.4%) developed gestational diabetes. Participants with gestational diabetes were older (P = 0.002), more often of parity ≥ 2, had higher systolic (P = 0.02) and diastolic blood pressure (P = 0.02) and were more likely to be black (P = 0.009). Amongst the blood biomarkers measured, plasma adiponectin alone remained independently associated with gestational diabetes in adjusted models (P = 0.002). The area under the receiver-operating curve for clinical factors alone (0.760) increased significantly (area under the curve 0.834, chi-square statistic (1) = 4.00, P = 0.046) with the addition of adiponectin., Conclusions: A combination of routinely measured clinical factors and adiponectin measured in the early second trimester in obese women may provide a useful approach to the prediction of gestational diabetes. Validation in a large prospective study is required to determine the usefulness of this algorithm in clinical practice., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Early spontaneous preterm birth is associated with inflammation/infection and shortening of the cervix. We hypothesised that cervico-vaginal production of trappin2/elafin (peptidase inhibitor 3) and cathelicidin antimicrobial peptide (cathelicidin), key components of the innate immune system, are altered in women who have a spontaneous preterm birth. The aim was to determine the relationship between cervico-vaginal fluid (CVF) trappin2/elafin and cathelicidin protein concentrations with cervical length in woman at risk of spontaneous preterm birth. Trappin2/elafin and cathelicidin were measured using ELISA in longitudinal CVF samples (taken between 13 to 30 weeks' gestation) from 74 asymptomatic high risk women (based on obstetric history) recruited prospectively. Thirty six women developed a short cervix (<25 mm) by 24 weeks' and 38 women did not. Women who developed a short cervix had 2.71 times higher concentrations of CVF trappin2/elafin from 14 weeks' versus those who did not (CI 1.94-3.79, p<0.0005). CVF trappin2/elafin before 24 weeks' was 1.79 times higher in women who had a spontaneous preterm birth <37 weeks' (CI: 1.05-3.05, p = 0.034). Trappin2/elafin (>200 ng/ml) measured between 14+0-14+6 weeks' of pregnancy predicted women who subsequently developed a short cervix (n = 11, ROC area = 1.00, p = 0.008) within 8 weeks. Cathelicidin was not predictive of spontaneous delivery. Vitamin D status did not correlate with CVF antimicrobial peptide concentrations. Raised CVF trappin2/elafin has potential as an early pregnancy test for prediction of cervical shortening and spontaneous preterm birth. This justifies validation in a larger cohort.

Objective: To quantify reporting errors, measure incidence of postpartum haemorrhage (PPH) and define risk factors for PPH (≥500 ml) and progression to severe PPH (≥1500 ml)., Design: Prospective observational study., Setting: Two UK maternity services., Population: Women giving birth between 1 August 2008 and 31 July 2009 (n = 10 213)., Methods: Weighted sampling with sequential adjustment by multivariate analysis., Main Outcome Measures: Incidence and risk factors for PPH and progression to severe PPH., Results: Errors in transcribing blood volume were frequent (14%) with evidence of threshold preference and avoidance. The incidences of PPH ≥500, ≥1500 and ≥2500 ml were 33.7% (95% CI 31.2-36.2), 3.9% (95% CI 3.3-4.6) and 0.8% (95% CI 0.6-1.0). New independent risk factors predicting PPH ≥ 500 ml included Black African ethnicity (adjusted odds ratio [aOR] 1.77, 95% CI 1.31-2.39) and assisted conception (aOR 2.93, 95% CI 1.30-6.59). Modelling demonstrated how prepregnancy- and pregnancy-acquired factors may be mediated through intrapartum events, including caesarean section, elective (aOR 24.4, 95% CI 5.53-108.00) or emergency (aOR 40.5, 95% CI 16.30-101.00), and retained placenta (aOR 21.3, 95% CI 8.31-54.7). New risk factors were identified for progression to severe PPH, including index of multiple deprivation (education, skills and training) (aOR 1.75, 95% CI 1.11-2.74), multiparity without caesarean section (aOR 1.65, 95% CI 1.20-2.28) and administration of steroids for fetal reasons (aOR 2.00, 95% CI 1.24-3.22)., Conclusions: Sequential, interacting, traditional and new risk factors explain the highest rates of PPH and severe PPH reported to date., (© 2014 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Background: Patients with coronary heart disease (CHD) who are depressed have an increased risk of further cardiac events and higher mortality., Aim: To use a patient generated instrument (PSYCHLOPS) to define categories of concerns in patients with CHD. To define the psychometric characteristics of patients in each category., Design and Setting: Cross-sectional study set in general practices in south London., Method: Of 3325 patients on the CHD registers in 15 general practices, 655 completed six baseline psychometric and functional instruments: PSYCHLOPS, HADS-Depression, HADS-Anxiety, Clinical Interview Schedule-Revised, SF12-Mental and SF12-Physical. Content analysis was used to categorise patients based on their main problem, as elicited by PSYCHLOPS. Mean psychometric scores were adjusted for confounding by age, sex, deprivation and ethnicity and calculated for each response category., Results: Response categories were: physical problems, both non-cardiac (23.2%) and cardiac (6.0%); social problems: relationship/family (18.2%), money (7.5%), work (3.1%); functional (9.8%); psychological (6.9%); miscellaneous (7.3%); 'no problem' (18.2%). The highest psychological distress scores were found in 'physical, cardiac' and 'psychological' categories. The 'no problem' category had significantly lower psychological distress and higher functional capacity than other categories., Conclusions: PSYCHLOPS enabled the identification of subtypes of CHD patients, based on a classification of self-reported problems. A high proportion of CHD patients report social problems. Psychological distress was highest in those reporting cardiac or psychological symptoms. Services should be aligned to the reported needs of patients., (© British Journal of General Practice 2014.)

Background: Increased prescribing of inhaled long-acting anti-muscarinic (LAMA) and combined inhaled long-acting β2-agonist and corticosteroid (LABA+ICS) drugs for the treatment of chronic obstructive pulmonary disease (COPD) has led to hopes of reduced hospital admissions from this disease., Aims: To investigate the impact of rising primary care prescribing of LAMA and LABA+ICS drugs on COPD admissions., Methods: This retrospective cohort study of general practice COPD admission and prescribing data between 2007 and 2010 comprised a representative group of 806 English general practices (population 5,264,506). Outcome measures were practice rates of COPD patient admissions and prescription costs of LAMA and LABA+ICS. General practice characteristics were based on the UK quality and outcomes framework., Results: Rates of COPD admissions remained stable from 2001 to 2010. Practice-prescribing volumes of LAMA per practice patient and LABA+ICS per practice patient increased by 61 and 26%, respectively, between 2007 and 2010. Correlation between costs of LAMA and those of LABA+ICS increased year on year, and was the highest in 2010 (Pearson's r=0.68; 95% confidence interval (CI) 0.64 to 0.72). Practice COPD admission rates were positively predicted by practice-prescribing volumes of LAMA (2010: B=1.23, 95% CI 0.61 to 1.85) and of LABA+ICS (2010: B=0.32, 95% CI 0.12 to 0.52) when controlling for practice list size, COPD prevalence and deprivation., Conclusion: The increase in the prescribing of LAMA and LABA+ICS inhalers was not associated with the predicted fall in hospital admission rates for COPD patients. The positive correlation between high practice COPD prescribing and high practice COPD admissions was not explained.

Objective: To provide an accurate assessment of complications of pregnancy in women with chronic hypertension, including comparison with population pregnancy data (US) to inform pre-pregnancy and antenatal management strategies., Design: Systematic review and meta-analysis., Data Sources: Embase, Medline, and Web of Science were searched without language restrictions, from first publication until June 2013; the bibliographies of relevant articles and reviews were hand searched for additional reports., Study Selection: Studies involving pregnant women with chronic hypertension, including retrospective and prospective cohorts, population studies, and appropriate arms of randomised controlled trials, were included., Data Extraction: Pooled incidence for each pregnancy outcome was reported and, for US studies, compared with US general population incidence from the National Vital Statistics Report (2006)., Results: 55 eligible studies were identified, encompassing 795,221 pregnancies. Women with chronic hypertension had high pooled incidences of superimposed pre-eclampsia (25.9%, 95% confidence interval 21.0% to 31.5 %), caesarean section (41.4%, 35.5% to 47.7%), preterm delivery <37 weeks' gestation (28.1% (22.6 to 34.4%), birth weight <2500 g (16.9%, 13.1% to 21.5%), neonatal unit admission (20.5%, 15.7% to 26.4%), and perinatal death (4.0%, 2.9% to 5.4%). However, considerable heterogeneity existed in the reported incidence of all outcomes (τ(2)=0.286-0.766), with a substantial range of incidences in individual studies around these averages; additional meta-regression did not identify any influential demographic factors. The incidences (the meta-analysis average from US studies) of adverse outcomes in women with chronic hypertension were compared with women from the US national population dataset and showed higher risks in those with chronic hypertension: relative risks were 7.7 (95% confidence interval 5.7 to 10.1) for superimposed pre-eclampsia compared with pre-eclampsia, 1.3 (1.1 to 1.5) for caesarean section, 2.7 (1.9 to 3.6) for preterm delivery <37 weeks' gestation, 2.7 (1.9 to 3.8) for birth weight <2500 g, 3.2 (2.2 to 4.4) for neonatal unit admission, and 4.2 (2.7 to 6.5) for perinatal death., Conclusions: This systematic review, reporting meta-analysed data from studies of pregnant women with chronic hypertension, shows that adverse outcomes of pregnancy are common and emphasises a need for heightened antenatal surveillance. A consistent strategy to study women with chronic hypertension is needed, as previous study designs have been diverse. These findings should inform counselling and contribute to optimisation of maternal health, drug treatment, and pre-pregnancy management in women affected by chronic hypertension.

Unlabelled: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, characterized by maternal pruritus and raised serum bile acids. Our objectives were to describe the epidemiology and pregnancy complications associated with severe ICP and to test the hypothesis that adverse perinatal outcomes are increased in these women. A prospective population-based case-control study with national coverage was undertaken using the UK Obstetric Surveillance System (UKOSS). Control data for comparison were obtained from women with healthy pregnancy outcome through UKOSS (n = 2,232), St Mary's Maternity Information System (n = 554,319), and Office for National Statistics (n = 668,195). The main outcome measures investigated were preterm delivery, stillbirth, and neonatal unit admission. In all, 713 confirmed cases of severe ICP were identified, giving an estimated incidence of 9.2 per 10,000 maternities. Women with severe ICP and a singleton pregnancy (n = 669) had increased risks of preterm delivery (164/664; 25% versus 144/2200; 6.5%; adjusted odds ratio [OR] 5.39, 95% confidence interval [CI] 4.17 to 6.98), neonatal unit admission (80/654; 12% versus 123/2192; 5.6%; adjusted OR 2.68, 95% CI 1.97 to 3.65), and stillbirth (10/664; 1.5% versus 11/2205; 0.5%; adjusted OR 2.58, 95% CI 1.03 to 6.49) compared to controls. Seven of 10 stillbirths in ICP cases were associated with coexisting pregnancy complications. These differences remained significant against national data. Risks of preterm delivery, meconium-stained amniotic fluid, and stillbirth rose with increasing maternal serum bile acid concentrations., Conclusion: In the largest prospective cohort study in severe ICP to date, we demonstrate significant increased risks of adverse perinatal outcomes, including stillbirth. Our findings support the case for close antenatal monitoring of pregnancies affected by severe ICP., (© 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.)