Summary Background Fetal growth restriction is a major determinant of adverse perinatal outcome. Screening procedures for fetal growth restriction need to identify small babies and then differentiate ...between those that are healthy and those that are pathologically small. We sought to determine the diagnostic effectiveness of universal ultrasonic fetal biometry in the third trimester as a screening test for small-for-gestational-age (SGA) infants, and whether the risk of morbidity associated with being small differed in the presence or absence of ultrasonic markers of fetal growth restriction. Methods The Pregnancy Outcome Prediction (POP) study was a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan. Women participating had clinically indicated ultrasonography in the third trimester as per routine clinical care and these results were reported as usual (selective ultrasonography). Additionally, all participants had research ultrasonography, including fetal biometry at 28 and 36 weeks' gestational age. These results were not made available to participants or treating clinicians (universal ultrasonography). We regarded SGA as a birthweight of less than the 10th percentile for gestational age and screen positive for SGA an ultrasonographic estimated fetal weight of less than the 10th percentile for gestational age. Markers of fetal growth restriction included biometric ratios, utero-placental Doppler, and fetal growth velocity. We assessed outcomes for consenting participants who attended research scans and had a livebirth at the Rosie Hospital (Cambridge, UK) after the 28 weeks' research scan. Findings Between Jan 14, 2008, and July 31, 2012, 4512 women provided written informed consent of whom 3977 (88%) were eligible for analysis. Sensitivity for detection of SGA infants was 20% (95% CI 15–24; 69 of 352 fetuses) for selective ultrasonography and 57% (51–62; 199 of 352 fetuses) for universal ultrasonography (relative sensitivity 2·9, 95% CI 2·4–3·5, p<0·0001). Of the 3977 fetuses, 562 (14·1%) were identified by universal ultrasonography with an estimated fetal weight of less than the 10th percentile and were at an increased risk of neonatal morbidity (relative risk RR 1·60, 95% CI 1·22–2·09, p=0·0012). However, estimated fetal weight of less than the 10th percentile was only associated with the risk of neonatal morbidity (pinteraction =0·005) if the fetal abdominal circumference growth velocity was in the lowest decile (RR 3·9, 95% CI 1·9–8·1, p=0·0001). 172 (4%) of 3977 pregnancies had both an estimated fetal weight of less than the 10th percentile and abdominal circumference growth velocity in the lowest decile, and had a relative risk of delivering an SGA infant with neonatal morbidity of 17·6 (9·2–34·0, p<0·0001). Interpretation Screening of nulliparous women with universal third trimester fetal biometry roughly tripled detection of SGA infants. Combined analysis of fetal biometry and fetal growth velocity identified a subset of SGA fetuses that were at increased risk of neonatal morbidity. Funding National Institute for Health Research, Medical Research Council, Sands, and GE Healthcare.
Summary Background The Apgar score has been used worldwide as an index of early neonatal condition for more than 60 years. With advances in health-care service provision, neonatal resuscitation, and ...infant care, its present relevance is unclear. The aim of the study was to establish the strength of the relation between Apgar score at 5 min and the risk of neonatal and infant mortality, subdivided by specific causes. Methods We linked routine discharge and mortality data for all births in Scotland, UK between 1992 and 2010. We restricted our analyses to singleton livebirths, in women aged over 10 years, with a gestational age at delivery between 22 and 44 weeks, and excluded deaths due to congenital anomalies or isoimmunisation. We calculated the relative risks (RRs) of neonatal and infant death of neonates with low (0–3) and intermediate (4–6) Apgar scores at 5 min referent to neonates with normal Apgar score (7–10) using binomial log-linear modelling with adjustment for confounders. Analyses were stratified by gestational age at birth because it was a significant effect modifier. Missing covariate data were imputed. Findings Complete data were available for 1 029 207 eligible livebirths. Across all gestational strata, low Apgar score at 5 min was associated with an increased risk of neonatal and infant death. However, the strength of the association (adjusted RR, 95% CI referent to Apgar 7–10) was strongest at term (p<0·0001). A low Apgar (0–3) was associated with an adjusted RR of 359·4 (95% CI 277·3–465·9) for early neonatal death, 30·5 (18·0–51·6) for late neonatal death, and 50·2 (42·8–59·0) for infant death. We noted similar associations of a lower magnitude for intermediate Apgar (4–6). The strongest associations were for deaths attributed to anoxia and low Apgar (0–3) for term infants (RR 961·7, 95% CI 681·3–1357·5) and preterm infants (141·7, 90·1–222·8). No association between Apgar score at 5 min and the risk of sudden infant death syndrome was noted at any gestational age (RR 0·6, 95% CI 0·1–4·6 at term; 1·2, 0·3–4·8 at preterm). Interpretation Low Apgar score at 5 min was strongly associated with the risk of neonatal and infant death. Our findings support its continued usefulness in contemporary practice. Funding None.
Stillbirths: recall to action in high-income countries Flenady, Vicki, Dr; Wojcieszek, Aleena M, BPsySci; Middleton, Philippa, PhD ...
The Lancet (British edition),
02/2016, Letnik:
387, Številka:
10019
Journal Article
Recenzirano
Odprti dostop
Summary Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best ...performing countries, 19 439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20–30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.
Stillbirth Smith, Gordon CS, Prof; Fretts, Ruth C, MD
Lancet,
11/2007, Letnik:
370, Številka:
9600
Journal Article, Book Review
Recenzirano
Summary In the UK, about one in 200 infants is stillborn, and rates of stillbirth have recently slightly increased. This recent rise might reflect increasing frequency of some important maternal risk ...factors for stillbirth, including nulliparity, advanced age, and obesity. Most stillbirths are related to placental dysfunction, which in many women is evident from the first half of pregnancy and is associated with fetal growth restriction. There is no effective screening test that has clearly shown a reduction in stillbirth rates in the general population. However, assessments of novel screening methods have generally failed to distinguish between effective identification of high-risk women and successful intervention for such women. Future research into stillbirth will probably focus on understanding the pathophysiology of impaired placentation to establish screening tests for stillbirth, and assessment of interventions to prevent stillbirth in women who screen positive.
Summary Background Stillbirth rates in high-income countries have shown little or no improvement over the past two decades. Prevention strategies that target risk factors could be important in rate ...reduction. This systematic review and meta-analysis was done to identify priority areas for stillbirth prevention relevant to those countries. Methods Population-based studies addressing risk factors for stillbirth were identified through database searches. The factors most frequently reported were identified and selected according to whether they could potentially be reduced through lifestyle or medical intervention. The numbers attributable to modifiable risk factors were calculated from data relating to the five high-income countries with the highest numbers of stillbirths and where all the data required for analysis were available. Odds ratios were calculated for selected risk factors, from which population-attributable risk (PAR) values were calculated. Findings Of 6963 studies initially identified, 96 population-based studies were included. Maternal overweight and obesity (body-mass index >25 kg/m2 ) was the highest ranking modifiable risk factor, with PARs of 8–18% across the five countries and contributing to around 8000 stillbirths (≥22 weeks' gestation) annually across all high-income countries. Advanced maternal age (>35 years) and maternal smoking yielded PARs of 7–11% and 4–7%, respectively, and each year contribute to more than 4200 and 2800 stillbirths, respectively, across all high-income countries. In disadvantaged populations maternal smoking could contribute to 20% of stillbirths. Primiparity contributes to around 15% of stillbirths. Of the pregnancy disorders, small size for gestational age and abruption are the highest PARs (23% and 15%, respectively), which highlights the notable role of placental pathology in stillbirth. Pre-existing diabetes and hypertension remain important contributors to stillbirth in such countries. Interpretation The raising of awareness and implementation of effective interventions for modifiable risk factors, such as overweight, obesity, maternal age, and smoking, are priorities for stillbirth prevention in high-income countries. Funding The Stillbirth Foundation Australia, the Department of Health and Ageing, Canberra, Australia, and the Mater Foundation, Brisbane, Australia.
Stillbirth rates in high-income countries declined dramatically from about 1940, but this decline has slowed or stalled over recent times. The present variation in stillbirth rates across and within ...high-income countries indicates that further reduction in stillbirth is possible. Large disparities (linked to disadvantage such as poverty) in stillbirth rates need to be addressed by providing more educational opportunities and improving living conditions for women. Placental pathologies and infection associated with preterm birth are linked to a substantial proportion of stillbirths. The proportion of unexplained stillbirths associated with under investigation continues to impede efforts in stillbirth prevention. Overweight, obesity, and smoking are important modifiable risk factors for stillbirth, and advanced maternal age is also an increasingly prevalent risk factor. Intensified efforts are needed to ameliorate the effects of these factors on stillbirth rates. Culturally appropriate preconception care and quality antenatal care that is accessible to all women has the potential to reduce stillbirth rates in high-income countries. Implementation of national perinatal mortality audit programmes aimed at improving the quality of care could substantially reduce stillbirths. Better data on numbers and causes of stillbirth are needed, and international consensus on definition and classification related to stillbirth is a priority. All parents should be offered a thorough investigation including a high-quality autopsy and placental histopathology. Parent organisations are powerful change agents and could have an important role in raising awareness to prevent stillbirth. Future research must focus on screening and interventions to reduce antepartum stillbirth as a result of placental dysfunction. Identification of ways to reduce maternal overweight and obesity is a high priority for high-income countries.
Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral ...CFTR gene therapy in patients with cystic fibrosis.
We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867.
Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups.
Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials.
Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.
Screening and prevention of stillbirth Smith, Gordon C.S., Prof
Best practice & research. Clinical obstetrics & gynaecology,
01/2017, Letnik:
38
Journal Article
Recenzirano
Odprti dostop
Abstract Stillbirth is delivery of a baby at or after 24 weeks of gestational age (UK definition) showing no signs of life. It affects almost 1 in 200 pregnancies and is the single major cause of ...perinatal death. Stillbirth is associated with a wide range of maternal demographic characteristics, but most of the variation in stillbirth risk is independent of these characteristics. Stillbirth is the end point of multiple processes, but the single most common cause is probably placental dysfunction. Stillbirth is associated with a range of biochemical and ultrasonic predictors, but there is limited evidence to support population based screening. However, the evidence based is weak due by use of poorly characterised screening tests, the failure to couple risk assessment with a clearly effective intervention for those who screen positive, and inadequate study sample sizes. Basic research needs to identify better predictors, and clinical trials need to adopt more rigorous methodology.
Abstract Background Reactive oxygen species (ROS), generated via the phagocyte NADPH oxidase cytochrome b558, are essential for effective immune responses to common and serious pathogens. The ...phagocyte NADPH oxidase is a multisubunit protein complex and deficiency of either the membrane bound or cytoplasmic components leads to chronic granulomatous disease, a serious and often fatal illness characterised by recurrent infections and autoimmunity. Moreover, abnormal generation of ROS has been implicated in the pathogenesis of multigenic autoimmune diseases such as systemic lupus erythematosus. Eros (essential for reactive oxygen species), encoded by bc017643 , is a novel transmembrane protein that is highly expressed in the immune system and highly conserved in evolution but has no previously identified function. Eros is an orthologue of the plant protein Ycf4, necessary for expression of proteins of the photosynthetic photosystem 1 complex, an NADPH oxio-reductase complex. We elucidated its role in infection in mice. Methods ROS are essential for host defence against the serious bacterial pathogen Salmonella enterica serovar Typhimurium. We screened individual knockout mice (Wellcome Trust Knockout mouse project) for susceptibility to salmonella infection. Having identified mice deficient in Eros as being highly susceptible to salmonella, we used ex-vivo approaches including reactive oxygen burst assays and western blot, to characterise their defect further. Findings We found that Eros was essential for host defence to infection. Eros was crucial for generating reactive oxygen species through regulation of the essential NADPH oxidase components, gp91 and p22. Eros-deficient mice expressed almost no gp91 and p22 in neutrophils and macrophages secondary to accelerated degradation in the absence of Eros. As a result Eros-deficient mice died rapidly after infection with salmonella or listeria. Eros also regulated the ROS-dependent formation of neutrophil extracellular traps and melanoma metastases. Interpretation We have found a a key role for Eros in regulating host defence. The finding that Eros-deficient mice lack gp91 and p22 at the protein, though not mRNA, level shows how these key components of the reatcive oxygen burst are protected from degradation and furthers our understanding of reactive oxygen burst biology. Eros is highly conserved between mouse and man so it is likely that it also has a crucial role in human immunity. Funding Wellcome Trust, Academy of Medical Sciences starter grant.
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