Meformin and insulin treatment prevent placental telomere attrition in boys exposed to maternal diabetes

Shortened leukocyte and placental telomeres associated with gestational diabetes mellitus (GDM) suggest this exposure triggers telomere attrition contributing to adverse outcomes. We applied high resolution Single Telomere Length Analysis (STELA) to placenta from GDM pregnancies with different treatment pathways to determine their effectiveness at preventing telomere attrition. Differences in telomere length between control (N = 69), GDM lifestyle intervention (n = 14) and GDM treated with metformin and/or insulin (n = 17) was tested by Analysis of Covariance (ANCOVA) followed by group comparisons using Fisher’s least significant difference. For male placenta only, there were differences in mean telomere length (F(2,54) = 4.98, P = 0.01) and percentage of telomeres under 5 kb (F(2,54) = 4.65, P = 0.01). Telomeres were shorter in the GDM lifestyle intervention group compared to both controls (P = 0.02) and medically treated pregnancies (P = 0.003). There were more telomeres under 5 kb in the GDM lifestyle intervention group compared to the other two groups (P = 0.03 and P = 0.004). Although further work is necessary, we suggest that early adoption of targeted medical treatment of GDM pregnancies where the fetus is known to be male may be an effective strategy for ameliorating adverse outcomes for children

Telomere length heterogeneity in placenta revealed with high-resolution telomere length analysis

Introduction Telomeres, are composed of tandem repeat sequences located at the ends of chromosomes and are required to maintain genomic stability. Telomeres can become shorter due to cell division and specific lifestyle factors. Critically shortened telomeres are linked to cellular dysfunction, senescence and aging. A number of studies have used low resolution techniques to assess telomere length in the placenta. In this study, we applied Single Telomere Length Analysis (STELA) which provides high-resolution chromosome specific telomere length profiles to ask whether we could obtain more detailed information on the length of individual telomeres in the placenta. Methods Term placentas (37–42 weeks) were collected from women delivering at University Hospital of Wales or Royal Gwent Hospital within 2 h of delivery. Multiple telomere-length distributions were determined using STELA. Intraplacental variation of telomere length was analysed (N = 5). Telomere length distributions were compared between labouring (N = 10) and non-labouring (N = 11) participants. Finally, telomere length was compared between female (N = 17) and male (N = 20) placenta. Results There were no significant influences of sampling site, mode of delivery or foetal sex on the telomere-length distributions obtained. The mean telomere length was 7.7 kb ranging from 5.0 kb to 11.7 kb across all samples (N = 42) and longer compared with other human tissues at birth. STELA also revealed considerable telomere length heterogeneity within samples. Conclusions We have shown that STELA can be used to study telomere length homeostasis in the placenta regardless of sampling site, mode of delivery and foetal sex. Moreover, as each amplicon is derived from a single telomeric molecule, from a single cell, STELA can reveal the full detail of telomere-length distributions, including telomeres within the length ranges observed in senescent cells. STELA thus provides a new tool to interrogate the relationship between telomere length and pregnancy complications linked to placental dysfunction

Telomere length heterogeneity in placenta revealed with high-resolution telomere length analysis

Introduction Telomeres, are composed of tandem repeat sequences located at the ends of chromosomes and are required to maintain genomic stability. Telomeres can become shorter due to cell division and specific lifestyle factors. Critically shortened telomeres are linked to cellular dysfunction, senescence and aging. A number of studies have used low resolution techniques to assess telomere length in the placenta. In this study, we applied Single Telomere Length Analysis (STELA) which provides high-resolution chromosome specific telomere length profiles to ask whether we could obtain more detailed information on the length of individual telomeres in the placenta. Methods Term placentas (37–42 weeks) were collected from women delivering at University Hospital of Wales or Royal Gwent Hospital within 2 h of delivery. Multiple telomere-length distributions were determined using STELA. Intraplacental variation of telomere length was analysed (N = 5). Telomere length distributions were compared between labouring (N = 10) and non-labouring (N = 11) participants. Finally, telomere length was compared between female (N = 17) and male (N = 20) placenta. Results There were no significant influences of sampling site, mode of delivery or foetal sex on the telomere-length distributions obtained. The mean telomere length was 7.7 kb ranging from 5.0 kb to 11.7 kb across all samples (N = 42) and longer compared with other human tissues at birth. STELA also revealed considerable telomere length heterogeneity within samples. Conclusions We have shown that STELA can be used to study telomere length homeostasis in the placenta regardless of sampling site, mode of delivery and foetal sex. Moreover, as each amplicon is derived from a single telomeric molecule, from a single cell, STELA can reveal the full detail of telomere-length distributions, including telomeres within the length ranges observed in senescent cells. STELA thus provides a new tool to interrogate the relationship between telomere length and pregnancy complications linked to placental dysfunction

Persistence of anxiety symptoms after elective caesarean delivery

Background In the UK, 11.8% of expectant mothers undergo an elective caesarean section (ELCS) representing 92 000 births per annum. It is not known to what extent this procedure has an impact on mental well-being in the longer term. Aims To determine the prevalence and postpartum progression of anxiety and depression symptoms in women undergoing ELCS in Wales. Method Prevalence of depression and anxiety were determined in women at University Hospital Wales (2015–16; n = 308) through completion of the Edinburgh Postnatal Depression Scale (EPDS; ≥13) and State-Trait Anxiety Inventory (STAI; ≥40) questionnaires 1 day prior to ELCS, and three postpartum time points for 1 year. Maternal characteristics were determined from questionnaires and, where possible, confirmed from National Health Service maternity records. Results Using these criteria the prevalence of reported depression symptoms was 14.3% (95% CI 10.9–18.3) 1 day prior to ELCS, 8.0% (95% CI 4.2–12.5) within 1 week, 8.7% (95% CI 4.2–13.8) at 10 weeks and 12.4% (95% CI 6.4–18.4) 1 year postpartum. Prevalence of reported anxiety symptoms was 27.3% (95% CI 22.5–32.4), 21.7% (95% CI 15.8–28.0), 25.3% (95% CI 18.5–32.7) and 35.1% (95% CI 26.3–44.2) at these same stages. Prenatal anxiety was not resolved after ELCS more than 1 year after delivery. Conclusions Women undergoing ELCS experience prolonged anxiety postpartum that merits focused clinical attention. Declaration of interest None

Falling Caesarean section rate and improving intra-partum outcomes: A prospective cohort study

Objective: To evaluate caesarean section (CS) rates and moderate to severe hypoxaemic ischaemic encephalopathy (HIE) rates with other core intra-partum outcomes following reconfiguration of maternity services in Cardiff, South Wales, UK. Design: Cohort study of births from 2006 to 2015. Settings: A University tertiary referral centre for foetal and maternal medicine with 6000 births/year, University Hospital of Wales, United Kingdom. Method: Data relating to births from 1 January 2006 to 31 December 2015 were extracted from the computerized maternity database on a yearly basis. Case notes of all mothers and babies for the same duration were hand searched for documentation of HIE. HIE data was also collected prospectively by neonatologist (SC) and obstetrician (PA). Main outcome measures: Incidence of caesarean section births, babies with moderate to severe HIE, instrumental vaginal births, obstetric anal sphincter injuries (OASIS) associated with instrumental delivery, and major post-partum haemorrhage (MPPH) of 2500 mL or more. Results: During this 10-year period, a downward trend in emergency CS rate was seen from 15.6% in 2006 to 10.5% in 2015, reducing total CS rate from 25.5% in 2006 to 21.2% in 2015. A downward trend in the incidence of moderate and severe HIE was seen over the same period. There was an increase in operative vaginal births (OVB) from 12.8% to 15%. The rate of spontaneous vaginal births (SVB) remained stable. The incidence of OASIS remained constant and MPPH rate has fallen. Conclusions: Following amalgamation of two medium sized obstetric units and the opening of a Midwifery Led Unit (MLU), core intrapartum outcomes have improved. Contributing factors are the introduction of regular multidisciplinary training with enhanced team working, compulsory education for obstetricians and midwives on cardiotocograph (CTG) interpretation, increased consultant presence on delivery suite, robust risk management systems and broad multidisciplinary agreement on clinical guidelines promoting vaginal birth

The Grown in Wales Study: Examining dietary patterns, custom birthweight centiles and the risk of delivering a small-for-gestational age (SGA) infant

Objectives Maternal lifestyles, including diet, have been linked to infant birthweight. However, customised birthweight centiles (CBWC), which more accurately identify small babies that have increased fetal growth restriction and are at higher risk of newborn morbidity and later life health complications, are rarely considered when studying maternal diet. This study investigated maternal dietary patterns and their impact on infant CBWC within a cohort of women living in South Wales. Methods This study utilised cross-sectional data from the longitudinal Grown in Wales (GiW) cohort. Women 18–45 years old were recruited the morning prior to an elective caesarean section (ELCS). Women completed a food frequency questionnaire (FFQ). Additional data on pregnancy and birth outcomes was extracted from medical notes. Data from 303 participants was analysed. Results ‘Western’ and ‘Health conscious dietary patterns were identified. The ‘Health Conscious’ dietary pattern was significantly associated with maternal BMI, age, education, income and exercise. Adjusted regression analyses indicated that greater adherence to a ‘Health Conscious’ dietary pattern was significantly associated with increased CBWC (AOR = 4.75 [95% CI: 1.17, 8.33] p = .010) and reduced risk of delivering a small-for-gestational age (SGA) infant (AOR = .51 [95% CI: .26, .99] p = .046). Conclusion A healthier diet was significantly associated with higher birthweight using CBWC and a reduced risk of delivering an SGA infant suggesting that birthweight will be improved in areas of Wales by focused support encouraging healthier dietary habits

Seasonal variation in salivary cortisol but not symptoms of depression and trait anxiety in pregnant women undergoing an elective caesarean section

Objectives Seasonal changes in mood and behaviour are commonly reported in the general population but considerably less is known regarding seasonality and pregnancy. This study investigated the relationship between seasons and depression and anxiety symptoms, salivary cortisol concentrations, custom birthweight centiles (CBWC) and placenta weight for pregnant women living in South Wales. Methods This study utilised data from the longitudinal Grown in Wales (GiW) cohort. Women were recruited at the presurgical elective caesarean section (ELCS) appointment, when they provided saliva samples and completed the Edinburgh Postnatal Depression Scale (EPDS) and trait subscale of the State-Trait Anxiety Inventory (STAI). Data on birthweight and placental weight was extracted from medical notes. Seasonal data was available for 316 participants. Results No association was identified between seasons and EPDS (p = .178), STAI scores (p = .544), CBWC (p = .683) or placental weight (p = .857). Significance was identified between seasons and salivary cortisol concentration (p<.001), with highest levels in autumn and winter. Adjusted linear regression identified spring (B=−.05, p=.007, 95% CI −.09, −.01) and summer (B=−.06, p = .001, 95% CI −09, −.02) compared to autumn, and spring (B=−.05, p=.009, 95% CI −.09, −.01) and summer (B=−.06, p=.002, 95% CI −.10, −.02) compared to winter to be associated with decreased cortisol concentrations. Conclusion This study found no association between season and maternally-reported mental health symptoms, birthweight by CBWC or placental weight but did between season and term salivary cortisol. This finding will have implications for studies that do not account for seasonality when using salivary cortisol as a biomarker

Symptoms of prenatal depression associated with shorter telomeres in female placenta

Background. Depression is a common mood disorder during pregnancy impacting one in every seven women. Children exposed to prenatal depression are more likely to be born at a low birth weight and develop chronic diseases later in life. A proposed hypothesis for this relationship between early exposure to adversity and poor outcomes is accelerated aging. Telomere length has been used as a biomarker of cellular aging. We used high-resolution telomere length analysis to examine the relationship between placental telomere length distributions and maternal mood symptoms in pregnancy. Methods. This study utilised samples from the longitudinal Grown in Wales (GiW) study. Women participating in this study were recruited at their presurgical appointment prior to a term elective caesarean section (ELCS). Women completed the Edinburgh Postnatal Depression Scale (EPDS) and trait subscale of the State-Trait Anxiety Inventory (STAI). Telomere length distributions were generated using single telomere length analysis (STELA) in 109 term placenta (37–42 weeks). Multiple linear regression was performed to examine the relationship between maternally reported symptoms of depression and anxiety at term and mean placental telomere length. Results: Prenatal depression symptoms were significantly negatively associated with XpYp telomere length in female placenta (B = −0.098, p = 0.026, 95% CI −0.184, −0.012). There was no association between maternal depression symptoms and telomere length in male placenta (B = 0.022, p = 0.586, 95% CI −0.059, 0.103). There was no association with anxiety symptoms and telomere length for either sex. Conclusion: Maternal prenatal depression is associated with sex-specific differences in term placental telomeres. Telomere shortening in female placenta may indicate accelerated placental agin

Medical terminations of pregnancy: A viable source of tissue for cell replacement therapy for neurodegenerative disorders

“Proof-of-principle” that cell replacement therapy works for neurodegeneration has been reported, but only using donor cells collected from fetal brain tissue obtained from surgical terminations of pregnancy. Surgical terminations of pregnancy represent an increasingly limited supply of donor cells due to the tendency towards performing medical termination in much of Europe. This imposes a severe constraint on further experimental and clinical cell transplantation research. Therefore, we explore here the feasibility of using medical termination tissue as a donor source. Products of conception were retrieved from surgical terminations over the last 7 years and from medical terminations over the last 2.5 years. The number of collections that yielded fetal tissue, viable brain tissue, and identifiable brain regions (ganglionic eminence, ventral mesencephalon, and neocortex) were recorded. We studied cell viability, cell physiological properties, and differentiation potential both in vitro and following transplantation into the central nervous system of rodent models of neurodegenerative disease. Within equivalent periods, we were able to collect substantially greater numbers of fetal remains from medical than from surgical terminations of pregnancy, and the medical terminations yielded a much higher proportion of identifiable and dissectible brain tissue. Furthermore, we demonstrate that harvested cells retain the capacity to differentiate into neurons with characteristics appropriate to the region from which they are dissected. We show that, contrary to widespread assumption, medical termination of pregnancy-derived fetal brain cells represent a feasible and more readily available source of human fetal tissue for experimental cell transplantation with the potential for use in future clinical trials in human neurodegenerative disease

Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis

BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. Intravenous antibiotics are commonly used in the treatment of acute deteriorations in symptoms (pulmonary exacerbations); however, recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. OBJECTIVES: To establish if intravenous antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short- and long-term clinical outcomes. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews and ongoing trials registers.Date of last search of Cochrane trials register: 27 July 2015. SELECTION CRITERIA: Randomised controlled trials and the first treatment cycle of cross-over studies comparing intravenous antibiotics (given alone or in an antibiotic combination) with placebo, inhaled or oral antibiotics for people with cystic fibrosis experiencing a pulmonary exacerbation. DATA COLLECTION AND ANALYSIS: The authors assessed studies for eligibility and risk of bias and extracted data. MAIN RESULTS: We included 40 studies involving 1717 participants. The quality of the included studies was largely poor and, with a few exceptions, these comprised of mainly small, inadequately reported studies.When comparing treatment with a single antibiotic to a combined antibiotic regimen, those participants receiving a combination of antibiotics experienced a greater improvement in lung function when considered as a whole group across a number of different measurements of lung function, but with very low quality evidence. When limited to the four placebo-controlled studies (n = 214), no difference was observed, again with very low quality evidence. With regard to the review's remaining primary outcomes, there was no effect upon time to next exacerbation and no studies in any comparison reported on quality of life. There were no effects on the secondary outcomes weight or adverse effects. When comparing specific antibiotic combinations there were no significant differences between groups on any measure. In the comparisons between intravenous and nebulised antibiotic or oral antibiotic (low quality evidence), there were no significant differences between groups on any measure. No studies in any comparison reported on quality of life. AUTHORS' CONCLUSIONS: The quality of evidence comparing intravenous antibiotics with placebo is poor. No specific antibiotic combination can be considered to be superior to any other, and neither is there evidence showing that the intravenous route is superior to the inhaled or oral routes. There remains a need to understand host-bacteria interactions and in particular to understand why many people fail to fully respond to treatment