My Baby's Movements: a stepped-wedge cluster-randomised controlled trial of a fetal movement awareness intervention to reduce stillbirths.

OBJECTIVE: The My Baby's Movements (MBM) trial aimed to evaluate the impact on stillbirth rates of a multifaceted awareness package (the MBM intervention). DESIGN: Stepped-wedge cluster-randomised controlled trial. SETTING: Twenty-seven maternity hospitals in Australia and New Zealand. POPULATION: Women with a singleton pregnancy without major fetal anomaly at ≥28 weeks of gestation from August 2016 to May 2019. METHODS: The MBM intervention was implemented at randomly assigned time points, with the sequential introduction of eight groups of between three and five hospitals at 4-monthly intervals. Using generalised linear mixed models, the stillbirth rate was compared in the control and the intervention periods, adjusting for calendar time, study population characteristics and hospital effects. MAIN OUTCOME MEASURES: Stillbirth at ≥28 weeks of gestation. RESULTS: There were 304 850 births with 290 105 births meeting the inclusion criteria: 150 053 in the control and 140 052 in the intervention periods. The stillbirth rate was lower (although not statistically significantly so) during the intervention compared with the control period (2.2/1000 versus 2.4/1000 births; aOR 1.18, 95% CI 0.93-1.50; P = 0.18). The decrease in stillbirth rate was greater across calendar time: 2.7/1000 in the first versus 2.0/1000 in the last 18 months. No increase in secondary outcomes, including obstetric intervention or adverse neonatal outcome, was evident. CONCLUSIONS: The MBM intervention did not reduce stillbirths beyond the downward trend over time. As a result of low uptake, the role of the intervention remains unclear, although the downward trend across time suggests some benefit in lowering the stillbirth rate. In this study setting, an awareness of the importance of fetal movements may have reached pregnant women and clinicians prior to the implementation of the intervention. TWEETABLE ABSTRACT: The My Baby's Movements intervention to raise awareness of decreased fetal movement did not significantly reduce stillbirth rates.

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.

A single meal has the potential to alter brain oxylipin content.

Our objective was to determine whether consumption of a single meal has the potential to alter brain oxylipin content. We examined the cerebrum of mice fed a single high-fat/high-sucrose Western meal or a low-fat/low-sucrose control meal, as well as fasted mice. We found no changes in fatty acid composition of cerebrum across the groups. The cerebral oxylipin profile of mice fed a Western meal is distinct from the profile of mice fed a low-fat/low-sucrose meal. Cerebral gene expression of cyclooxygenase 1, cyclooxygenase 2, and epoxide hydrolase 1 were elevated in Western meal-fed mice compared to low-fat/low-sucrose meal-fed mice. Mice that consumed either meal had lower gene expression of cytochrome P450, family 2, subfamily j, polypeptide 12 than fasted mice. Our data in this hypothesis-generating study indicates that the composition of a single meal has the potential to alter brain oxylipins and the gene expression of the enzymes responsible for their production.

My Baby's Movements: a stepped wedge cluster randomised controlled trial to raise maternal awareness of fetal movements during pregnancy study protocol.

BACKGROUND: Stillbirth is a devastating pregnancy outcome that has a profound and lasting impact on women and families. Globally, there are over 2.6 million stillbirths annually and progress in reducing these deaths has been slow. Maternal perception of decreased fetal movements (DFM) is strongly associated with stillbirth. However, maternal awareness of DFM and clinical management of women reporting DFM is often suboptimal. The My Baby's Movements trial aims to evaluate an intervention package for maternity services including a mobile phone application for women and clinician education (MBM intervention) in reducing late gestation stillbirth rates. METHODS/DESIGN: This is a stepped wedge cluster randomised controlled trial with sequential introduction of the MBM intervention to 8 groups of 3-5 hospitals at four-monthly intervals over 3 years. The target population is women with a singleton pregnancy, without lethal fetal abnormality, attending for antenatal care and clinicians providing maternity care at 26 maternity services in Australia and New Zealand. The primary outcome is stillbirth from 28 weeks' gestation. Secondary outcomes address: a) neonatal morbidity and mortality; b) maternal psychosocial outcomes and health-seeking behaviour; c) health services utilisation; d) women's and clinicians' knowledge of fetal movements; and e) cost. 256,700 births (average of 3170 per hospital) will detect a 30% reduction in stillbirth rates from 3/1000 births to 2/1000 births, assuming a significance level of 5%. Analysis will utilise generalised linear mixed models. DISCUSSION: Maternal perception of DFM is a marker of an at-risk pregnancy and commonly precedes a stillbirth. MBM offers a simple, inexpensive resource to reduce the number of stillborn babies, and families suffering the distressing consequences of such a loss. This large pragmatic trial will provide evidence on benefits and potential harms of raising awareness of DFM using a mobile phone app. TRIAL REGISTRATION: ACTRN12614000291684. Registered 19 March 2014. VERSION: Protocol Version 6.1, February 2018.

Effects of macrophage depletion on characteristics of cervix remodeling and pregnancy in CD11b-dtr mice.

To test the hypothesis that macrophages are essential for remodeling the cervix in preparation for birth, pregnant homozygous CD11b-dtr mice were injected with diphtheria toxin (DT) on days 14 and 16 postbreeding. On day 15 postbreeding, macrophages (F4/80+) were depleted in cervix and kidney, but not in liver, ovary, or other non-reproductive tissues in DT-compared to saline-treated dtr mice or wild-type controls given DT or saline. Within 24 h of DT-treatment, the density of cell nuclei and macrophages declined in cervix stroma in dtr mice versus controls, but birefringence of collagen, as an indication of extracellular cross-linked structure, remained unchanged. Only in the cervix of DT-treated dtr mice was an apoptotic morphology evident in macrophages. DT-treatment did not alter the sparse presence or morphology of neutrophils. By day 18 postbreeding, macrophages repopulated the cervix in DT-treated dtr mice so that the numbers were comparable to that in controls. However, at term, evidence of fetal mortality without cervix ripening occurred in most dtr mice given DT-a possible consequence of treatment effects on placental function. These findings suggest that CD11b+ F4/80+ macrophages are important to sustain pregnancy and are required for processes that remodel the cervix in preparation for parturition.

Activity behaviors in lean and morbidly obese pregnant women.

Interventions to increase physical activity in pregnancy are challenging for morbidly obese women. Targeting sedentary behaviors may be a suitable alternative to increase energy expenditure. We aimed to determine total energy expenditure, and energy expended in sedentary activities in morbidly obese and lean pregnant women. We administered the Pregnancy Physical Activity Questionnaire (nonobjective) and the Actical accelerometer (objective) to morbidly obese (BMI ≥ 40 kg/m²) and lean (BMI ≤ 25 Kg/m²) pregnant women recruited in early (<24 weeks), and late (≥24 weeks) gestation. Data are mean (SD). Morbidly obese pregnant women reported expending significantly more energy per day in early (n = 140 vs 109; 3198.4 (1847.1) vs 1972.3 (10284.8) Kcal/d, P < .0001) and late (n = 104 vs 64; 3078.2 (1356.5) vs 1947.5 (652.0) Kcal/d, P < .0001) pregnancy, and expended significantly more energy in sedentary activities, in early (816.1 (423.5) vs 540.1 (244.9) Kcal/d, P < .0001) and late (881.6 (455.4) vs 581.1 (248.5) Kcal/d, P < .0001) pregnancy, than lean pregnant women. No differences were observed in the proportion of energy expended sedentary between lean and morbidly obese pregnant women. The greater total energy expenditure in morbidly obese pregnant women was corroborated by Actical accelerometer in early (n = 14 per group, obese 1167.7 (313.6) Kcal; lean 781.1 (210.1) Kcal, P < .05), and in late (n = 14 per group, obese 1223.6 (351.5) Kcal; lean 893.7 (175.9) Kcal, P < .05) pregnancy. In conclusion, non-objective and objective measures showed morbidly obese pregnant women expended more energy per day than lean pregnant. Further studies are needed to determine whether sedentary behaviors are a suitable target for intervention in morbidly obese pregnancy.

Immune cell and transcriptomic analysis of the human decidua in term and preterm parturition.

STUDY QUESTION: Is labour, both at term and preterm, associated with alterations in decidual lymphocyte densities and widespread changes to the decidual transcriptome? SUMMARY ANSWER: The onset of parturition, both at term and preterm, is associated with widespread gene expression changes in the decidua, many of which are related to inflammatory signalling, but is not associated with changes in the number of any of the decidual lymphocyte populations examined. WHAT IS KNOWN ALREADY: Given its location, directly at the maternal-foetal interface, the decidua is likely to play a pivotal role in the onset of parturition, however, the molecular events occurring in the decidua in association with the onset of labour, both at term and preterm, remain relatively poorly defined. Using flow cytometry and microarray analysis, the present study aimed to investigate changes to the immune cell milieu of the decidua in association with the onset of parturition and define the decidual gene signature associated with term and preterm labour (PTL). STUDY DESIGN, SIZE, DURATION: This study used decidual samples collected from 36 women across four clinical groups: term (38-42 weeks of gestation) not in labour, TNL; term in labour, TL; preterm (<35 weeks of gestation)not in labour, PTNL; and preterm in labour, PTL. PARTICIPANTS/MATERIALS, SETTING, METHODS: Decidual lymphocytes were isolated from fresh decidual tissue collected from women in each of our four patient groups and stained with a panel of antibodies (CD45, CD3, CD19, CD56, CD4, CD8 and TCRVα24-Jα18) to investigate lymphocyte populations present in the decidua (TNL, n = 8; TL, n = 7; PTNL, n = 5; PTL, n = 5). RNA was extracted from decidual tissue and subjected to Illumina HT-12v4.0 BeadChip expression microarrays (TNL, n = 11; TL, n = 8; PTNL, n = 7; PTL, n = 10). Quantitative real-time PCR (qRT-PCR) was used to validate the microarray results. MAIN RESULTS AND THE ROLE OF CHANCE: The relative proportions of decidual lymphocytes (T cells, NK cells, B cells and invariant natural killer (iNKT) cells) were unaffected by either gestation or labour status. However, we found elevated expression of the non-classical MHC-protein, CD1D, in PTL decidua samples (P < 0.05), suggesting the potential for increased activation of decidual invariant NKT (iNKT) cells in PTL. Both term and PTL were associated with widespread gene expression changes, particularly related to inflammatory signalling. Up-regulation of candidate genes in TL (IL-6, PTGS2, ATF3, IER3 and TNFAIP3) and PTL (CXCL8, MARCO, LILRA3 and PLAU) were confirmed by qRT-PCR analysis. LARGE SCALE DATA: Microarray data are available at www.ebi.ac.uk/arrayexpress under accession number E-MTAB-5353. LIMITATIONS REASONS FOR CAUTION: Whilst no changes in lymphocyte number were observed across our patient samples, we did not investigate the activation state of any of the immune cell sub-populations examined, therefore, it is possible that the function of these cells may be altered in association with labour onset. Additionally, the results of our transcriptomic analyses are descriptive and at this stage, we cannot prove direct causal link with the up-regulation of any of the genes examined and the onset of either term or PTL. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that the onset of parturition is associated with widespread changes to the decidual transcriptome, and there are distinct gene expression changes associated with term and PTL. We confirmed that an inflammatory signature is present within the decidua, and we also report the up-regulation of several genes involved in regulating the inflammatory response. The identification of genes involved in regulating the inflammatory response may provide novel molecular targets for the development of new, more effective therapies for the prevention of preterm birth (PTB). Such targets are urgently required. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by Medical Research Council (grant number MR/L002657/1) and Tommy's, the baby charity. Jane Norman has had research grants from the charity Tommy's and from the National Institute for Health Research on PTB during the lifetime of this project. Jane Norman also sits on a data monitoring committee for GSK for a study on PTB prevention and her institution receives financial recompense for this. The other authors do not have any conflicts of interest to declare.

Written versus verbal consent: a qualitative study of stakeholder views of consent procedures used at the time of recruitment into a peripartum trial conducted in an emergency setting.

BACKGROUND: Obtaining prospective written consent from women to participate in trials when they are experiencing an obstetric emergency is challenging. Alternative consent pathways, such as gaining verbal consent at enrolment followed, later, by obtaining written consent, have been advocated by some clinicians and bioethicists but have received little empirical attention. We explored women's and staff views about the consent procedures used during the internal pilot of a trial (GOT-IT), where the protocol permitted staff to gain verbal consent at recruitment. METHODS: Interviews with staff (n = 27) and participating women (n = 22). Data were analysed thematically and interviews were cross-compared to identify differences and similarities in participants' views about the consent procedures used. RESULTS: Women and some staff highlighted benefits to obtaining verbal consent at trial enrolment, including expediting recruitment and reducing the burden on those left exhausted by their births. However, most staff with direct responsibility for taking consent expressed extreme reluctance to proceed with enrolment until they had obtained written consent, despite being comfortable using verbal procedures in their clinical practice. To account for this resistance, staff drew a strong distinction between research and clinical care and suggested that a higher level of consent was needed when recruiting into trials. In doing so, staff emphasised the need to engage women in reflexive decision-making and highlighted the role that completing the consent form could play in enabling and evidencing this process. While most staff cited their ethical responsibilities to women, they also voiced concerns that the absence of a signed consent form at recruitment could expose them to greater risk of litigation were an individual to experience a complication during the trial. Inexperience of recruiting into peripartum trials and limited availability of staff trained to take consent also reinforced preferences for obtaining written consent at recruitment. CONCLUSIONS: While alternative consent pathways have an important role to play in advancing emergency medicine research, and may be appreciated by potential recruits, they may give rise to unintended ethical and logistical challenges for staff. Staff would benefit from training and support to increase their confidence and willingness to recruit into trials using alternative consent pathways. TRIAL REGISTRATION: This qualitative research was undertaken as part of the GOT-IT Trial (trial registration number: ISCRTN 88609453 ). Date of registration 26/03/2014.

Prenatal exposure to very severe maternal obesity is associated with adverse neuropsychiatric outcomes in children.

BACKGROUND: Prenatal maternal obesity has been linked to adverse childhood neuropsychiatric outcomes, including increased symptoms of attention deficit hyperactivity disorder (ADHD), internalizing and externalizing problems, affective disorders and neurodevelopmental problems but few studies have studied neuropsychiatric outcomes among offspring born to very severely obese women or assessed potential familial confounding by maternal psychological distress. METHOD: We evaluated neuropsychiatric symptoms in 112 children aged 3-5 years whose mothers had participated in a longitudinal study of obesity in pregnancy (50 very severe obesity, BMI ⩾40 kg/m2, obese class III and 62 lean, BMI 18.5-25 kg/m2). The mothers completed the Conners' Hyperactivity Scale, Early Symptomatic Syndrome Eliciting Neurodevelopmental Clinical Examination Questionnaire (ESSENCE-Q), Child's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), and Child Behavior Checklist (CBCL) to assess child neuropsychiatric symptoms. Covariates included child's sex, age, birthweight, gestational age, socioeconomic deprivation levels, maternal age, parity, smoking status during pregnancy, gestational diabetes and maternal concurrent symptoms of anxiety and depression assessed using State Anxiety of Spielberger State-Trait Anxiety Index (STAI) and General Health Questionnaire (GHQ), respectively. RESULTS: Children exposed to prenatal maternal very severe obesity had significantly higher scores in the Conners' Hyperactivity Scale; ESSENCE-Q; total sleep problems in CSHQ; hyperactivity, conduct problems and total difficulties scales of the SDQ; higher externalizing and total problems, anxious/depressed, aggressive behaviour and other problem syndrome scores and higher DSM-oriented affective, anxiety and ADHD problems in CBCL. Prenatal maternal very severe obesity remained a significant predictor of child neuropsychiatric problems across multiple scales independent of demographic factors, prenatal factors and maternal concurrent symptoms of anxiety and depression. CONCLUSIONS: Prenatal maternal very severe obesity is a strong predictor of increased neuropsychiatric problems in early childhood.

Maternal gestational weight gain and offspring's risk of cardiovascular disease and mortality.

OBJECTIVE: To examine the effect of maternal gestational weight gain (GWG) on adult offspring mortality, cardiovascular morbidity and cerebrovascular morbidity. METHODS: The Aberdeen Children of the Nineteen Fifties (ACONF) is a population-based cohort of adults born in Aberdeen, Scotland between 1950 and 1956. GWG of the mothers of cohort members was extracted from original birth records and linked to the data on offspring morbidity and mortality up to 2011 obtained from Scottish national records. HRs for cardiovascular events and mortality in offspring according to maternal weight gain in pregnancy were estimated adjusting for maternal and offspring confounders using a restricted cubic spline model. RESULTS: After exclusions, 3781 members of the original ACONF cohort were analysed. Of these, 103 (2.7%) had died, 169 (4.5%) had suffered at least one cardiovascular event and 73 (1.9%) had had a hospital admission for cerebrovascular disease. Maternal weight gain of 1 kg/week or more was associated with increased risk of cerebrovascular event in the offspring (adjusted HR 2.70 (95% CI 1.19 to 6.12)). There was no association seen between GWG and offspring's all-cause mortality or cardiovascular event. Adult offspring characteristics (smoking, body mass index (BMI) and diabetes) were strongly associated with each outcome. CONCLUSIONS: Maternal GWG above 0.9 kg/week may increase the risk of cerebrovascular disease in the adult offspring, but not all-cause mortality or cardiovascular disease. Health and lifestyle factors such as smoking, BMI and diabetes in the adult offspring had a stronger influence than maternal and birth characteristics on their mortality and morbidity.

Physical activity in pregnant women with Class III obesity: A qualitative exploration of attitudes and behaviours.

OBJECTIVE: To explore the barriers and facilitators to physical activity and lifestyle interventions in pregnant women with Class III obesity (body mass index >40 kg/m(2)). DESIGN: Qualitative study using in-depth, semi-structure interviews framed by the Theory of Planned Behaviour. Semi-structured, in-depth interviews were conducted using a topic guide. Data analysis was undertaken using a Framework Approach and was informed by the theory of planned behaviour. Recruitment and analysis continued until data saturation was reached. SETTING: Participants were recruited from an antenatal clinic for women with Class III obesity. PARTICIPANTS: Pregnant women (n=13) with Class III obesity. MEASUREMENTS AND OUTCOMES: Three major themes emerged from the data analysis: having a healthy lifestyle awareness, complex barriers to lifestyle changes and having personalised solutions to promote healthy lifestyle. Women were aware of the benefits of physical activity during pregnancy but had complex barriers to engaging with activity. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: future lifestyle interventions for women with Class III in pregnancy should take into account individual, societal and support barriers towards weight management and lifestyle choices in pregnancy. Programs that provide personalised support which are sensitive to the specific physical and psychological needs of women with Class III obesity which focus on the benefits and safety of physical activity for both mother and baby may be more likely to be successful. Further research is needed to explore the feasibility and acceptability of tailored programs.

Associations of mood symptoms with ante- and postnatal weight change in obese pregnancy are not mediated by cortisol.

BACKGROUND: Both maternal obesity and disordered mood have adverse effects on pregnancy outcome. We hypothesized that maternal very severe obesity (SO) is associated with increased anxiety and depression (A&D) symptoms during pregnancy, with adverse effects on gestational weight gain (GWG), postpartum mood and postpartum weight retention (PPWR) and explored any mediation by circulating glucocorticoids. METHOD: We measured A&D symptoms with validated questionnaires at weeks 17 and 28 of pregnancy and 3 months postpartum in 135 lean [body mass index (BMI) ⩽25 kg/m2] and 222 SO (BMI ⩾40 kg/m2) pregnant women. Fasting serum cortisol was measured by radioimmunoassay; GWG and PPWR were recorded. RESULTS: A&D symptoms were higher in the SO group during pregnancy and postpartum despite adjusting for multiple confounders including previous mental health diagnosis (p < 0.05), and were non-linearly correlated with total GWG (anxiety R 2 = 0.06, p = 0.037; depression R 2 = 0.09, p = 0.001). In the SO group only, increased maternal anxiety (ß = 0.33, p = 0.03) and depression (ß = 0.19, p = 0.04) symptoms at week 17 of pregnancy were associated with increased PPWR, independent of total GWG and breastfeeding. Anxiety symptoms at week 28 of pregnancy, but not depression, were non-linearly correlated with serum cortisol level at week 36 of pregnancy (R 2 = 0.06, p = 0.02). Cortisol did not mediate the link between A&D symptoms and GWG. CONCLUSIONS: Maternal SO was associated with increased A&D symptoms, and with adverse effects on GWG and PPWR independent of circulating glucocorticoids. Strategies to optimize GWG and postpartum weight management in SO women should include assessment and management of maternal mood in early pregnancy.

Crosstalk between monocytes and myometrial smooth muscle in culture generates synergistic pro-inflammatory cytokine production and enhances myocyte contraction, with effects opposed by progesterone.

Both term and preterm parturition are characterized by an influx of macrophages and neutrophils into the myometrium and cervix, with co-incident increased peripheral blood monocyte activation. Infection and inflammation are strongly implicated in the pathology of preterm labour (PTL), with progesterone considered a promising candidate for its prevention or treatment. In this study, we investigated the effect of monocytes on myometrial smooth muscle cell inflammatory cytokine production both alone and in response to LPS, a TLR4 agonist used to trigger PTL in vivo. We also investigated the effect of monocytes on myocyte contraction. Monocytes, isolated from peripheral blood samples from term pregnant women, were cultured alone, or co-cultured with PHM1-41 myometrial smooth muscle cells, for 24 h. In a third set of experiments, PHM1-41 myocytes were cultured for 24 h in isolation. Cytokine secretion was determined by ELISA or multiplex assays. Co-culture of monocytes and myocytes led to synergistic secretion of pro-inflammatory cytokines and chemokines including IL-6, IL-8 and MCP-1, with the secretion being further enhanced by LPS (100 ng/ml). The synergistic secretion of IL-6 and IL-8 from co-cultures was mediated in part by direct cell-cell contact, and by TNF. Conditioned media from co-cultures stimulated contraction of PHM1-41 myocytes, and the effect was inhibited by progesterone. Both progesterone and IL-10 inhibited LPS-stimulated IL-6 and IL-8 secretion from co-cultures, while progesterone also inhibited chemokine secretion. These data suggest that monocytes infiltrating the myometrium at labour participate in crosstalk that potentiates pro-inflammatory cytokine secretion, an effect that is enhanced by LPS, and can augment myocyte contraction. These effects are all partially inhibited by progesterone.

15-epi-lipoxin A4 reduces the mortality of prematurely born pups in a mouse model of infection-induced preterm birth.

Preterm birth remains the leading cause of neonatal mortality and morbidity worldwide. There are currently few effective therapies and therefore an urgent need for novel treatments. Although there is much focus on trying to alter gestation of delivery, the primary aim of preterm birth prevention therapies should be to reduce prematurity related mortality and morbidity. Given the link between intrauterine infection and inflammation and preterm labour (PTL), we hypothesized that administration of lipoxins, key anti-inflammatory and pro-resolution mediators, could be a useful novel treatment for PTL. Using a mouse model of infection-induced PTL, we investigated whether 15-epi-lipoxin A4 could delay lipopolysaccharide (LPS)-induced PTL and reduce pup mortality. On D17 of gestation mice (n = 9-12) were pretreated with vehicle or 15-epi-lipoxin A4 prior to intrauterine administration of LPS or PBS. Although pretreatment with 15-epi-lipoxin A4 did not delay LPS-induced PTL, there was a significant reduction in the mortality amongst prematurely delivered pups (defined as delivery within 36 h of surgery) in mice treated with 15-epi-lipoxin A4 prior to LPS treatment, compared with those receiving LPS alone (P < 0.05). Quantitative real-time (QRT)-PCR analysis of utero-placental tissues harvested 6 h post-treatment demonstrated that 15-epi-lipoxin A4 treatment increased Ptgs2 expression in the uterus, placenta and fetal membranes (P < 0.05) and decreased 15-Hpgd expression (P < 0.05) in the placenta and uterus, suggesting that 15-epi-lipoxin A4 may regulate the local production and activity of prostaglandins. These data suggest that augmenting lipoxin levels could be a useful novel therapeutic option in the treatment of PTL, protecting the fetus from the adverse effects of infection-induced preterm birth.

Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.

BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Multiple pregnancies following assisted reproductive technologies--a happy consequence or double trouble?

The association between assisted reproduction technologies (ART) and multiple pregnancy is well-established, with a multiple birth rate of 24% in ART pregnancies. Multiple pregnancy is associated with significantly increased maternal and perinatal morbidity and mortality, as well as increased costs to the National Health Service. Evidence relating to the obstetric outcomes of ART twins versus naturally conceived twins is discussed in this review. Methods to reduce the risk of multiple births including elective single embryo transfer and multifetal pregnancy reduction are also discussed.

How should we test for nonsevere heritable platelet function disorders?

Heritable platelet function disorders (HPFD) are a heterogeneous group of bleeding disorders with diverse clinical and laboratory characteristics. In contrast to the severe phenotype disorders, Glanzmann thrombasthenia and Bernard-Soulier syndrome, most nonsevere HPFD are incompletely characterized. This is a consequence of the poor standardization of diagnostic tests and of the lack of consensus about diagnostic criteria for the different subgroups of nonsevere HPFD. Distinguishing patients who have a nonsevere HPFD from those who do not is an essential first step in diagnosis which may be aided by bleeding assessment tools and screening tests such as the Platelet Function Analyser-100. However, high diagnostic accuracy can only be achieved with both light transmission aggregation (LTA) and secretion tests, for which streamlined agonist panels may be of similar utility to extended panels. Standardization of the methodology of these tests and quality assurance are essential for robust diagnosis. Identification of which platelet pathway is defective in patients with nonsevere HPFD is also usually possible with LTA and secretion tests. This strategy also sometimes enables exact diagnosis by implicating a single candidate protein and gene. Next-generation sequencing may offer a rapid approach to diagnosis of nonsevere HPFD, although rigorous strategies must be adopted to distinguish causative gene defects from bystander variations.