Expression and activity of the Toll-like receptor family in the term and preterm human placenta.

Toll like receptors (TLR) have emerged as key upstream mediators of inflammation at many tissue sites in humans. Parturition is considered an inflammatory process so it was hypothesised that TLR activity within gestation-associated tissues, such as the placenta, might have an important role in the initiation and/or maintenance of normal term labour and in various pathological states of pregnancy such as infection associated preterm labour.Expression of transcripts for TLR1-10 was confirmed in term (>37 weeks of gestation) human placentas collected in the absence of labour (elective caesarean sections, termnon-laboured) and after the completion of labour at term (normal vaginal delivery, termlaboured,) and preterm ( <37 weeks gestation, preterm delivery). Explants of placental tissue were cultured in vitro in the presence of ligands for TLR 1-9 (an agonist of TLR 10 has not yet been identified). Cytokine (TNFa, IL-6, IL-8 & IL-10) production into the culture supernatants was then measured using ELISA.Reactivity to all agonists except CpG oligonucleotides was observed in all the three groups studied indicating that, other than TLR9, all of the receptors studied yielded functional responses. Placentas collected after the completion of labour (term laboured; n=17) had significantly more LPS (TLR4 agonist) and R848 (TLR7/8) agonist induced TNFa than those obtained in the absence of labour (term non-laboured", n=17). In contrast, gene expression analysis revealed that transcripts for TLR2 and TLR5 only were significantly elevated in association with labour. These findings indicate that there is no relationship between changes in mRNA expression and function of these receptors within the placenta.The study of placentas collected following preterm spontaneous vaginal delivery (preterm svd\ n=10) compared with those obtained after term laboured (n=17) revealed that significantly less TNFa and IL-6 were produced by placentas following preterm delivery in response to all TLR agonists. In contrast, the expression of TLR transcripts was found not to be statistically different for any of the TLRsl-10 in these two groups.Thus the human term placenta expresses a variety of functional TLRs and whilst LPS and R848 mediated TNFa increase at term labour, more detailed analysis of contributing cell types and signalling molecules is required to elucidate the role of this family of receptors in parturition

Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial

Background Severe early-onset fetal growth restriction can lead to a range of adverse outcomes including fetal or neonatal death, neurodisability, and lifelong risks to the health of the affected child. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide, which leads to vasodilatation of the uterine vessels and might improve fetal growth in utero. Methods We did this superiority, placebo-controlled randomised trial in 19 fetal medicine units in the UK. We used random computer allocation (1:1) to assign women with singleton pregnancies between 22 weeks and 0 days' gestation and 29 weeks and 6 days' gestation and severe early-onset fetal growth restriction to receive either sildenafil 25 mg three times daily or placebo until 32 weeks and 0 days' gestation or delivery. We stratified women by site and by their gestational age at randomisation (before week 26 and 0 days or at week 26 and 0 days or later). We defined fetal growth restriction as a combination of estimated fetal weight or abdominal circumference below tenth percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days. This study is registered with BioMed Central, number ISRCTN 39133303. Findings Between Nov 21, 2014, and July 6, 2016, we recruited 135 women and randomly assigned 70 women to sildenafil and 65 women to placebo. We found no difference in the median randomisation to delivery interval between women assigned to sildenafil (17 days [IQR 7–24]) and women assigned to placebo (18 days [8–28]; p=0·23). Livebirths (relative risk [RR] 1·06, 95% CI 0·84 to 1·33; p=0·62), fetal deaths (0·89, 0·54 to 1·45; p=0·64), neonatal deaths (1·33, 0·54 to 3·28; p=0·53), and birthweight (−14 g,–100 to 126; p=0·81) did not differ between groups. No differences were found for any other secondary outcomes. Eight serious adverse events were reported during the course of the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Interpretation Sildenafil did not prolong pregnancy or improve pregnancy outcomes in severe early-onset fetal growth restriction and therefore it should not be prescribed for this indication outside of research studies with explicit participants' consent. Funding National Institute for Health Research and Medical Research Council

The Preterm Clinical Network (PCN) Database: a web-based systematic method of collecting data on the care of women at risk of preterm birth

Background: Despite much research effort, there is a paucity of conclusive evidence in the field of preterm birth prediction and prevention. The methods of monitoring and prevention strategies offered to women at risk vary considerably around the UK and depend on local maternity care provision. It is becoming increasingly recognised that this experience and knowledge, if captured on a larger scale, could be a utilized as a valuable source of evidence for others. The UK Preterm Clinical Network (UKPCN) was established with the aim of improving care and outcomes for women at risk of preterm birth through the sharing of a wealth of experience and knowledge, as well as the building of clinical and research collaboration. The design and development of a bespoke internet-based database was fundamental to achieving this aim. Method: Following consultation with UKPCN members and agreement on a minimal dataset, the Preterm Clinical Network (PCN) Database was constructed to collect data from women at risk of preterm birth and their children. Information Governance and research ethics committee approval was given for the storage of historical as well as prospectively collected data. Collaborating centres have instant access to their own records, while use of pooled data is governed by the PCN Database Access Committee. Applications are welcomed from UKPCN members and other established research groups. The results of investigations using the data are expected to provide insights into the effectiveness of current surveillance practices and preterm birth interventions on a national and international scale, as well as the generation of ideas for innovation and research. To date, 31 sites are registered as Data Collection Centres, four of which are outside the UK. Conclusion: This paper outlines the aims of the PCN Database along with the development process undertaken from the initial idea to live launch

Endometrial resection mandates reliable contraception thereafter - a case report of placenta increta following endometrial ablation.

Placenta increta complicated pregnancy in a woman with a history of endometrial resection. Placentation in women with prior endometrial ablation carries a high risk for placenta accreta, increta and percreta. Contraceptive measures must be implemented after endometrial ablation and pursued until proven menopause, even in women who develop amenorrhoea postoperatively

Expression and activity of Toll-like receptors 1-9 in the human term placenta and changes associated with labor at term.

Inflammatory processes are involved in the initiation and maintenance of labor, suggesting that Toll-like receptor (TLR) activity within gestation-associated tissues, such as the placenta, might contribute to the process of parturition. Expression of transcripts for TLR1-TLR10 was examined in term (>37 wk of gestation) human placentas collected in the absence of labor (elective caesarean sections; ECS; n = 11) and after the completion of labor (normal vaginal delivery; NVD; n = 12). Placental explants were cultured in the presence of agonists for TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9, and cytokine production after 24 h was examined. All placentas expressed transcripts for TLR1-TLR10. Reactivity to all agonists except CpG oligonucleotides was observed, indicating that, other than TLR9, all of the receptors studied yielded functional responses. Placental explants prepared from NVD placentas (n = 17) produced significantly more TNFA in response to lipopolysaccharide (TLR4 agonist) and resiquimod (TLR7/8 agonist) than explants from ECS placentas (n = 17). In contrast, gene expression analysis revealed that only transcripts for TLR2 and TLR5 were significantly elevated in association with labor. The human term placenta expresses a variety of functional TLRs, indicating that this family of receptors has an important role in parturition via as yet undetermined cell types and signaling pathways

Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management.

Intravenous iron is widely used for the treatment of iron deficiency anemia when oral iron is inappropriate, ineffective or poorly tolerated. Acute hypersensitivity reactions during iron infusions are very rare but can be life-threatening. This paper reviews their frequency, pathogenesis and risk factors, and provides recommendations about their management and prevention. Complement activation-related pseudo-allergy triggered by iron nanoparticles is probably a more frequent pathogenetic mechanism in acute reactions to current formulations of intravenous iron than is an immunological IgE-mediated response. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, severe atopy, and possibly systemic inflammatory diseases. Early pregnancy is a contraindication to iron infusions, while old age and serious co-morbidity may worsen the impact of acute reactions if they occur. Management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff