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Introduction and Hypothesis: Vaginal childbirth is associated with pelvic floor muscle (PFM) damage in a third of women. The biomechanics prediction, detection and management of PFM damage remain poorly understood. We sought in this pilot study to determine whether quantifying PFM stiffness postnatally by vaginal elastometry, in women attending a perineal trauma clinic (PTC) within 6 months of obstetric anal sphincter injury, correlates with their antecedent labour characteristics, pelvic floor muscle damage, or urinary/bowel/sexual symptoms, to inform future definitive prospective studies., Methods: In this pilot study, we measured postnatal PFM stiffness by vaginal elastometry in 54 women. A subset of participants (n = 14) underwent magnetic resonance imaging (MRI) to define any levator ani (LA) muscle defects from vaginal childbirth. We investigated the association of PFM stiffness with demographics, labour and delivery characteristics, clinical features and MRI evidence of LA damage., Results: Raised maternal BMI was associated with reduced pelvic floor stiffness (r = -0.4; p < 0.01). Higher stiffness values were associated with forceps delivery for delayed second stage of labour (n = 14) vs non-forceps vaginal delivery (n = 40; 630 ± 40 N/m vs 500 ± 30 N/m; p < 0.05), and a non-significant trend towards longer duration of the second stage of labour. Women with urinary, bowel or sexual symptoms (n = 37) demonstrated higher pelvic floor stiffness values than those without (570 ± 30 N/m vs 450 ± 40 N/m; p < 0.05)., Conclusions: A history of delayed second stage of labour and forceps delivery was associated with higher PFM stiffness values in the postnatal period. Whether high pelvic muscle stiffness antenatally is a risk factor for instrumental vaginal delivery and LA avulsion is unknown.

Objective: To analyze a cohort of clinically unexplained stillbirths (CUS) referred for postmortem., Study Design: In total, 258 CUS were referred for full postmortem between 2009 and 2015. Relevant Condition at Death (ReCoDe) classification was applied. Statistical analysis included chi-square test and multiple logistic regression., Results: In all, 386 ReCoDe categories identified corresponded to: fetus (99); umbilical cord (48); placenta (165); amniotic fluid (55), and mother (1). No condition was identified in 18 cases. Prevalent conditions were placental insufficiency (101 cases, 39%) and fetal growth restriction (96 cases, 37%), frequently presenting together (41 cases, 15.9%). Significant associations were found between fetal growth restriction and gestational age, asymmetrical fetal growth and placental insufficiency., Conclusions: In total, 60.5% of CUS were diagnosed at postmortem to have fetal growth restriction and/or placental insufficiency. The mean gestational age of death in which these conditions presented was 32.7 weeks and 35.5 weeks, respectively, suggesting a critical time-frame to monitor to potentially reduce stillbirth occurrence.

Pre-eclampsia (PE) is characterized by an exaggerated systemic inflammatory response and generalized endothelial dysfunction. We have recently demonstrated that fibrinogen, an endogenous ligand of Toll-like receptor (TLR) 4, activates monocytes from women with pre-eclampsia (Al-ofi et al., 2014). Using an experimental co-culture model of primary human monocytes (derived from 9 women with PE (GA=33.18±5.8) and 9 normotensive pregnant women, NP (GA=33.15±4.0)) and human umbilical venous endothelial cells (HUVECs), we compared the effects of fibrinogen and lipopolysaccharide (LPS, bacterial ligand to TLR4) on the expression levels of inflammatory cytokines (IL-6 and IL-1β), chemokines (IL-8 and MCP-1), and anti-angiogenic factor (soluble fms-like tyrosine kinase-1,sFLT-1), as well as the soluble vascular cell adhesion molecule-1 (sVCAM-1). Cytokines, VEGF and sVCAM-1 were measured in the supernatant media by cytometric array. The levels of sFLT-1 were measured by ELISA. Fibrinogen induced greater expression levels of IL-1β and VCAM-1 from PE HUVEC-monocyte co-culture than from NP HUVEC-monocyte co-culture (P<0.05), similar to the effects of LPS. In contrast, unlike LPS, fibrinogen suppressed IL-6, IL-8, MCP-1 and sFLT-1 production by co-cultures that included PE monocytes compared to those with NP monocytes (P<0.05). In conclusion, fibrinogen promotes monocyte-endothelial cell adhesion and angiogenesis and suppresses the expression of some inflammatory markers in pre-eclampsia. Although the physiological implications of these intriguing observations are unclear our findings suggest that fibrinogen contributes to the regulation of cell adhesion, angiogenesis and inflammation by mechanisms not wholly dependent on TLR4 stimulation., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Pelvic infections and sexually transmitted diseases place a burden on health resources and may be associated with premature birth. The mechanisms by which the female reproductive tract (FRT) combats these infections remain ill understood, but are likely to involve the pattern recognition Toll-like receptors (TLR). We sought to compare the expression of TLR-2 and -4 by human pregnant and non-pregnant ectocervical epithelium as a prelude to the investigation of the function of these receptors in this tissue during pregnancy. Using the techniques of reverse-transcriptase polymer chain reaction (RT-PCR) and immunohistochemistry, the gene and protein expression of TLR-2 and -4 were studied in the biopsies of ectocervix obtained from non-pregnant premenopausal women (n=21) undergoing hysterectomy, women in the first trimester of pregnancy undergoing non-medically indicated suction pregnancy termination (n=6), and women at term undergoing elective caesarean section (n=11). The expression of TLR2 and TLR4 genes and proteins were upregulated in early and late pregnant ectocervical epithelium, compared with non-pregnant tissue. These findings suggest that the upregulation of TLR2 and TLR4 in the lower FRT may play a key role in the modulation of the innate immune and inflammatory mechanisms of the ectocervix during pregnancy, interacting with other neuroendocrine factors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Pre-eclampsia (PE) remains the leading cause of pregnancy-associated mortality and morbidity, urging the need for a better understanding of its aetiology and pathophysiological progression. A key characteristic of PE is a systemic, exaggerated, inflammatory condition involving abnormal cytokine levels in serum, altered immune cell phenotype and Th1/Th2-type immunological imbalance. However, it is unknown how this heightened inflammatory condition manifests. We previously reported increased expression of the lipopolysaccharide receptor, Toll-like receptor 4 (TLR4), on monocytes from PE patients compared with normotensive, pregnant patients (NP). This upregulation of TLR4 on PE monocytes was accompanied by a hyper-responsiveness to bacterial TLR4 ligands. To determine whether non-microbial, endogenous TLR4 ligands also activate monocytes from PE patients, we investigated the expression of host-derived TLR4 ligands and the response of monocytes to these endogenous ligands. Plasma levels of fibrinogen - but not fibronectin or heparan sulphate - were higher in PE patients than in NP. Exposure to fibrinogen was associated with significantly increased production of inflammatory cytokines by monocytes from PE patients. Interestingly, this effect was not observed with NP monocytes. Our findings suggest that the fibrinogen-TLR4 axis might play an important role in the atypical activation of monocytes observed in PE patients that may contribute to the exaggerated inflammatory condition., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Defective implantation is a mechanism for recurrent pregnancy loss (RPL). We sought to determine whether the serum expression of human relaxin-2 (RLX) is impaired in women with a history of RPL., Study Design: Employing a prospective case-controlled design we studied 20 pregnant women with a history of RPL and 20 age-matched women with no history of RPL (NRPL). We measured serum relaxin-2 levels by ELISA at 6-8, 10-12, 20, and 34 weeks gestation and in cord blood, and maternal uterine artery Doppler resistance index (RI) at >or=10 weeks gestation., Results: Relaxin rose to a peak at 12 weeks, and gradually declined towards term. At all gestations, women with a history of RPL had lower RLX levels than women without. At 10-12 weeks gestation, uterine artery RI correlated with serum RLX for both RPL and NRPL. In the NRPL group at 10-12 weeks the presence of a notched waveform was associated with higher RLX levels than the absence of a notch (mean 2.1 ng/ml vs. 1.3 ng/ml, P<0.05) and also at 20 weeks (2.1 ng/ml vs. 0.95 ng/ml, P<0.05) but no such difference was seen in the RPL group. Umbilical venous RLX was 4-fold higher in the RPL group than the NRPL group., Conclusion: Women with a history of RPL demonstrate attenuated levels of serum RLX across all pregnancy trimesters. How dysregulated RLX metabolism may contribute to adverse pregnancy outcome in RPL requires further investigation.

Objectives: The primary objective is to determine whether intrauterine vesicoamniotic shunting for fetal bladder outflow obstruction, compared with conservative, noninterventional care, improves prenatal and perinatal mortality and renal function. The secondary objectives are to determine if shunting for fetal bladder outflow obstruction improves perinatal morbidity, to determine if improvement in outcomes is related to prognostic assessment at diagnosis and, if possible, derive a prognostic risk index and to determine the safety and long-term efficacy of shunting., Design: A multicentre randomised controlled trial (RCT)., Setting: Fetal medicine units., Population: Pregnant women with singleton, male fetus with isolated lower urinary tract obstruction (LUTO)., Methods: Following ultrasound diagnosis of LUTO in a male fetus and exclusion of other structural and chromosomal anomalies, participation in the trial will be discussed with the mother and written information given. Consent for participation in the trial will be taken and the mother randomised via the internet to either insertion of a vesicoamniotic shunt or expectant management. During pregnancy, both groups will be followed with regular ultrasound scans looking at viability, renal measurements and amniotic fluid volume. Following delivery, babies will be followed up by paediatric nephrologists/urologists at 4-6 weeks, 12 months and 3 and 5 years to assess renal function via serum creatinine, renal ultrasound and need for dialysis/transplant., Main Outcome Measures: The main outcome measures will be perinatal mortality rates and renal function at 4-6 weeks and 12 months measured via serum creatinine, renal ultrasound and need for dialysis/transplant., Funding: Wellbeing of Women. ESTIMATED COMPLETION DATE: September 2010. TRIAL ALGORITHM: [flowchart: see text].

In humans, the factors that govern the switch from myometrial quiescence to coordinated contractions at the initiation of labor are not well defined. The onset of parturition is itself associated with increases in a number of proinflammatory mediators, many of which are regulated by the nuclear factor kappaB (NF-kappaB) family of transcription factors. Recently, we have provided evidence that the RelA NF-kappaB subunit associates with protein kinase A in pregnant myometrial tissue, suggesting links with the Galphas/cAMP/protein kinase A pathway. TNFalpha is a potent activator of NF-kappaB, and levels of this cytokine are increased within the myometrium at term. In the current study, using primary cultures of myometrial cells, TNFalpha was observed to repress expression of Galphas while, at the same time, stimulating NF-kappaB activity. Furthermore, this effect could be replicated by exposure to bacterial lipopolysaccharide and exogenous expression of RelA. Moreover, TNFalpha was seen to repress endogenous Galphas mRNA expression as judged by RT-PCR analyses. Using the chromatin immunoprecipitation assay, we show that RelA did not bind directly to the Galphas promoter. Significantly, expression of a coactivator protein, cAMP response element binding protein binding protein, relieved RelA-induced down-regulation of Galphas expression. Together, these data suggest that, in human myometrium, repression of the Galphas gene by NF-kappaB occurs through a non-DNA binding mechanism involving competition for limiting amounts of cellular coactivator proteins including cAMP response element binding protein binding protein.