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1.  New research models and novel signal analysis in studies on preterm labor: a key to progress? 
BMC Pregnancy and Childbirth  2007;7(Suppl 1):S6.
Preterm labor affects up to 20% of pregnancies, is considered a main cause of associated neonatal morbidity and mortality and is responsible for neonatal care costs of multimillion euros. In spite of that, the commercial market for this clinical indication is rather limited, which may be also related to high liability. Consequently, with only a few exceptions, preterm labor is not in the orbit of great interest of the pharmaceutical industry. Coordinated effort of research community may bring the change and help required to reduce the influence of this multifactorial syndrome on society. Between the novel techniques that are being explored in a SAFE (The Special Non-Invasive Advances in Fetal and Neonatal Evaluation Network) group, there are new research models of preterm labor as well as novel methodology of analysis of biological signals. In this article, we briefly describe new clinical and nonclinical human models of preterm labor as well as summarize some novel methods of data processing and analysis that may be used in the context of preterm labor.
doi:10.1186/1471-2393-7-S1-S6
PMCID: PMC1892063  PMID: 17570166
2.  Introduction to the special issue from the proceedings of the 2006 International Workshop on Virtual Reality in Rehabilitation 
New technologies are rapidly having a great impact on the development of novel rehabilitation interventions. One of the more popular of these technological advances is virtual reality. The wide range of applications of this technology, from immersive environments to tele-rehabilitation equipment and care, lends versatility to its use as a rehabilitation intervention. But increasing access to this technology requires that we further our understanding about its impact on a performer. The International Workshop on Virtual Reality in Rehabilitation (IWVR), now known as Virtual Rehabilitation 2007, is a conference that emerged from the need to discover how virtual reality could be applied to rehabilitation practice. Individuals from multiple disciplines concerned with the development, transmission, and evaluation of virtual reality as a technology applied to rehabilitation attend this meeting to share their work. In this special issue of the Journal of NeuroEngineering and Rehabilitation we are sharing some of the papers presented at the 2006 meeting of IWVR with the objective of offering a description of the state of the art in this research field. A perusal of these papers will provide a good cross-section of the emerging work in this area as well as inform the reader about new findings relevant to research and practice in rehabilitation.
doi:10.1186/1743-0003-4-18
PMCID: PMC1891302  PMID: 17553159
3.  Birth order, gestational age, and risk of delivery related perinatal death in twins: retrospective cohort study 
BMJ : British Medical Journal  2002;325(7371):1004.
Objective
To determine whether twins born second are at increased risk of perinatal death because of complications during labour and delivery.
Design
Retrospective cohort study.
Setting
Scotland, 1992 and 1997.
Participants
All twin births at or after 24 weeks' gestation, excluding twin pairs in which either twin died before labour or delivery or died during or after labour and delivery because of congenital abnormality, non-immune hydrops, or twin to twin transfusion syndrome.
Main outcome measure
Delivery related perinatal deaths (deaths during labour or the neonatal period).
Results
Overall, delivery related perinatal deaths were recorded for 23 first twins only and 23 second twins only of 1438 twin pairs born before 36 weeks (preterm) by means other than planned caesarean section (P>0.99). No deaths of first twins and nine deaths of second twins (P=0.004) were recorded among the 2436 twin pairs born at or after 36 weeks (term). Discordance between first and second twins differed significantly in preterm and term births (P=0.007). Seven of nine deaths of second twins at term were due to anoxia during the birth (2.9 (95% confidence interval 1.2 to 5.9) per 1000); five of these deaths were associated with mechanical problems with the second delivery following vaginal delivery of the first twin. No deaths were recorded among 454 second twins delivered at term by planned caesarean section.
Conclusions
Second twins born at term are at higher risk than first twins of death due to complications of delivery. Previous studies may not have shown an increased risk because of inadequate categorisation of deaths, lack of statistical power, inappropriate analyses, and pooling of data about preterm births and term births.
What is already known on this topicIt is difficult to assess the wellbeing of second twins during labourDeliveries of second twins are at increased risk of mechanical problems, such as cord prolapse and malpresentation, after vaginal delivery of first twinsIncreased risks of perinatal death in second twins have not been shown, but the methods of these studies were flawedWhat this study addsSecond twins delivered at term are at increased risk of delivery related perinatal deathsIntrapartum anoxia caused 75% of these deaths in second twins, and most of these resulted from mechanical problems after vaginal delivery of first twinsPlanned caesarean section of twins at term may prevent perinatal deaths
PMCID: PMC131015  PMID: 12411358
4.  Proceedings of the Second International Workshop on Advances in Electrocorticography 
Epilepsy & behavior : E&B  2011;22(4):10.1016/j.yebeh.2011.09.028.
The Second International Workshop on Advances in Electrocorticography (ECoG) was convened in San Diego, CA, USA, on November 11–12, 2010. Between this meeting and the inaugural 2009 event, a much clearer picture has been emerging of cortical ECoG physiology and its relationship to local field potentials and single-cell recordings. Innovations in material engineering are advancing the goal of a stable long-term recording interface. Continued evolution of ECoG-driven brain–computer interface technology is determining innovation in neuroprosthetics. Improvements in instrumentation and statistical methodologies continue to elucidate ECoG correlates of normal human function as well as the ictal state. This proceedings document summarizes the current status of this rapidly evolving field.
doi:10.1016/j.yebeh.2011.09.028
PMCID: PMC3847909  PMID: 22036287
Electrocorticography; Brain–computer interface; High-frequency oscillations; Brain mapping; Seizure detection; Gamma-frequency electroencephalography; Neuroprosthetics; Subdural grid
5.  Proceedings of the 1994 Canadian Clinical Practice Guidelines Network Workshop 
A workshop on the Clinical Practice Guidelines (CPG) Network was held in Ottawa on Oct. 31 and Nov. 1, 1994. Five plenary sessions focused on CPGs and the roles of organizations, priority setting, dissemination and implementation, evaluation, and establishment of a network of individuals and organizations active in the CPG field. In general, the participants identified consumers as important stakeholders in CPG processes and agreed that there was a role for national coordination and information gathering, however, local and regional bodies have a role in CPG development, dissemination and implementation. Burden of illness and likeliness that the guidelines would affect the burden were key criteria for setting priorities. Eighteen high-priority topics were identified for CPG development and dissemination. Methods to enhance the effectiveness of dissemination and implementation were identified: improved funding, enhanced research and decreased duplication of effort. Barriers to CPG evaluation were lack of funding and inadequate data sources. Voluntary self-audit was the preferred evaluation method. The participants agreed on three important functions of the network: facilitation, cooperation and communication, operation of a central CPG information centre, and provision of expertise in CPG processes. They also agreed to the use of an existing organization as a secretariat for the network, with a voluntary, informal membership of all those interested.
PMCID: PMC1488167  PMID: 8529185
6.  A Computational Model of Lipopolysaccharide-Induced Nuclear Factor Kappa B Activation: A Key Signalling Pathway in Infection-Induced Preterm Labour 
PLoS ONE  2013;8(7):e70180.
Preterm birth is the single biggest cause of significant neonatal morbidity and mortality, and the incidence is rising. Development of new therapies to treat and prevent preterm labour is seriously hampered by incomplete understanding of the molecular mechanisms that initiate labour at term and preterm. Computational modelling provides a new opportunity to improve this understanding. It is a useful tool in (i) identifying gaps in knowledge and informing future research, and (ii) providing the basis for an in silico model of parturition in which novel drugs to prevent or treat preterm labour can be “tested”. Despite their merits, computational models are rarely used to study the molecular events initiating labour. Here, we present the first attempt to generate a dynamic kinetic model that has relevance to the molecular mechanisms of preterm labour. Using published data, we model an important candidate signalling pathway in infection-induced preterm labour: that of lipopolysaccharide (LPS) -induced activation of Nuclear Factor kappa B. This is the first model of this pathway to explicitly include molecular interactions upstream of Nuclear Factor kappa B activation. We produced a formalised graphical depiction of the pathway and built a kinetic model based on ordinary differential equations. The kinetic model accurately reproduced published in vitro time course plots of Lipopolysaccharide-induced Nuclear Factor kappa B activation in mouse embryo fibroblasts. In this preliminary work we have provided proof of concept that it is possible to build computational models of signalling pathways that are relevant to the regulation of labour, and suggest that models that are validated with wet-lab experiments have the potential to greatly benefit the field.
doi:10.1371/journal.pone.0070180
PMCID: PMC3736540  PMID: 23936158
7.  Contribution of preterm delivery to perinatal mortality. 
British Medical Journal  1976;2(6042):965-968.
A detailed retrospective analysis was made of the records of 486 preterm infants, who accounted for 5-1% of all births during 1973 and 1974. Whereas preterm delivery did not contribute to perinatal mortality in terms of stillbirth, it outweighed all other causes in terms of early neonatal deaths. Preterm birth was responsible for 85% of the early neonatal deaths not due to lethal congenital deformities. Early neonatal mortality rates were closely linked both to gestational age and birth weight and to the reason for preterm birth. Early neonatal mortality was high (97 per 1000) when preterm labour was spontaneous, whether or not associated with material or fetal disease or with multiple pregnancy, but low (27 per 1000) when preterm delivery was elective. Preventing spontaneous preterm labour would considerably reduce neonatal mortality in our community.
PMCID: PMC1689290  PMID: 974709
8.  Imaging referral guidelines in Europe: now and in the future—EC Referral Guidelines Workshop Proceedings 
Insights into Imaging  2013;5(1):9-13.
Abstract
As an integral part of the European Commission (EC) Imaging Referral Guidelines Project a 1.5-day workshop was held in Vienna on 20–21 September, 2012. At this workshop, models and good practices regarding the appropriateness and use of imaging referral guidelines (Guidelines) in Europe and worldwide were presented, together with the results of a survey of Guidelines in Europe. The latter included ideas, innovations and wishes for future Community action.
Main messages
Recommendations for future Community action:Stronger measures should be taken by the EC and the European competent authorities for making Guidelines available and used in all EU member states.Evidence-based Guidelines with separate guidance for children should be issued or endorsed by a trusted European organisation.Educational initiatives and electronic requesting in connection with clinical decision support (CDS) systems should be used to improve the implementation of Guidelines.Monitoring of Guidelines implementation and use should be by clinical audit, particularly external audit, but also by local/internal audit.
Electronic supplementary material
The online version of this article (doi:10.1007/s13244-013-0299-8) contains supplementary material, which is available to authorised users.
doi:10.1007/s13244-013-0299-8
PMCID: PMC3948903  PMID: 24338616
9.  Prediction of survival for preterm births by weight and gestational age: retrospective population based study 
BMJ : British Medical Journal  1999;319(7217):1093-1097.
Objective
To produce current data on survival of preterm infants.
Design
Retrospective population based study.
Setting
Trent health region.
Subjects
All European and Asian live births, stillbirths, and late fetal losses from 22 to 32 weeks' gestation, excluding those with major congenital malformations, in women resident in the Trent health region between 1 January 1994 and 31 December 1997.
Main outcome measures
Birth weight and gestational age specific survival for both European and Asian infants (a) known to be alive at the onset of labour, and (b) admitted for neonatal care.
Results
738 deaths occurred in 3760 infants born between 22 and 32 weeks' gestation during the study period, giving an overall survival rate of 80.4%. The survival rate for the 3489 (92.8%) infants admitted for neonatal care was 86.6%. For European infants known to be alive at the onset of labour, significant variations in gestation specific survival by birth weight emerged from 24 weeks' gestation: survival ranged from 9% (95% confidence interval 7% to 13%) for infants of birth weight 250-499 g to 21% (16% to 28%) for those of 1000-1249 g. At 27 weeks' gestation, survival ranged from 55% (49% to 61%) for infants of birth weight 500-749 g (below the 10th centile) to 80% (76% to 85%) for those of 1250-1499 g. Infants who were large for dates (⩾27 weeks' gestation) had a slightly reduced, but not significant, predicted survival. Similar survival rates were observed for Asian infants. The odds ratio for the survival of infants from a multiple birth compared with singleton infants was 1.4 (1.1 to 1.8). Survival graphs for infants admitted for neonatal care are presented by sex.
Conclusion
Easy to use birth weight and gestational age specific predicted survival graphs for preterm infants facilitate decision making for clinicians and parents. It is important that these graphs are representative, are produced for a geographically defined population, and are not biased towards the outcomes of particular centres. Such graphs, produced in two stages, allow for the changing pattern of survival of infants from the start of the intrapartum period to immediately after admission for neonatal care.
Key messagesBirth weight and gestational age specific predicted survival graphs for preterm infants facilitate decision making for clinicians and parentsSurvival graphs should be representative and not biased towards the outcomes of particular centresPeriod specific graphs allow for the changing pattern of survival from the start of the intrapartum period to the immediate period after admission for neonatal careCauses of preterm delivery in singletons may lead to a poorer survival rate (controlled for gestation and birth weight) than those precipitated by multiple pregnancySurvival graphs need regular updating to allow for improvements in survival of infants
PMCID: PMC28258  PMID: 10531097
10.  Prenatal Imaging: Ultrasonography and Magnetic Resonance Imaging 
Obstetrics and gynecology  2008;112(1):145-157.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop on September 18–19, 2006, to summarize the available evidence on the role and performance of current fetal imaging technology and to establish a research agenda. Ultrasonography is the imaging modality of choice for pregnancy evaluation due to its relatively low cost, real-time capability, safety, and operator comfort and experience. First-trimester ultrasonography extends the available window for fetal observation and raises the possibility of performing an early anatomic survey. Three-dimensional ultrasonography has the potential to expand the clinical application of ultrasonography by permitting local acquisition of volumes and remote review and interpretation at specialized centers. New advances allow performance of fetal magnetic resonance imaging (MRI) without maternal or fetal sedation, with improved characterization and prediction of prognosis of certain fetal central nervous system anomalies such as ventriculomegaly when compared with ultrasonography. Fewer data exist on the usefulness of fetal MRI for non–central nervous system anomalies.
doi:10.1097/01.AOG.0000318871.95090.d9
PMCID: PMC2788813  PMID: 18591320
11.  Proceedings of the Indo-U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival 
Cancer Medicine  2013;2(1):108-115.
With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo-U.S. collaborative Workshop focusing on “Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment” was conducted at the Moffitt Cancer Center, 29–31 May 2012. Funded by the Indo-U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge (agents, molecular targets, biomarkers, approaches, target populations, regulatory standards, priorities, resources) of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo-U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop.
doi:10.1002/cam4.42
PMCID: PMC3797562  PMID: 24279005
Biologics; botanicals; cancer; chemoprevention; drug development
12.  Posterior Uterine Rupture Causing Fetal Expulsion into the Abdominal Cavity: A Rare Case of Neonatal Survival 
Introduction. Uterine rupture is a potentially catastrophic complication of vaginal birth after caesarean section. We describe the sixth case of posterior uterine rupture, with intact lower segment scar, and the first neonatal survival after expulsion into the abdominal cavity with posterior rupture. Case Presentation. A multiparous woman underwent prostaglandin induction of labour for postmaturity, after one previous caesarean section. Emergency caesarean section for bradycardia revealed a complete posterior uterine rupture, with fetal and placental expulsion. Upon delivery, the baby required inflation breaths only. The patient required a subtotal hysterectomy but returned home on day 5 postnatally with her healthy baby. Discussion. Vaginal birth after caesarean section constitutes a trial of labour, and the obstetrician must be reactive to labour events. Posterior uterine rupture is extremely rare and may occur without conventional signs. Good maternal and fetal outcome is possible with a prompt, coordinated team response.
doi:10.1155/2011/426127
PMCID: PMC3335479  PMID: 22567509
13.  The Effect of Changing Patterns of Obstetric Care in Scotland (1980–2004) on Rates of Preterm Birth and Its Neonatal Consequences: Perinatal Database Study 
PLoS Medicine  2009;6(9):e1000153.
Jane Norman and colleagues analyzed linked perinatal surveillance data in Scotland and find that between 1980 and 2004 increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births.
Background
Rates of preterm birth are rising worldwide. Studies from the United States and Latin America suggest that much of this rise relates to increased rates of medically indicated preterm birth. In contrast, European and Australian data suggest that increases in spontaneous preterm labour also play a role. We aimed, in a population-based database of 5 million people, to determine the temporal trends and obstetric antecedents of singleton preterm birth and its associated neonatal mortality and morbidity for the period 1980–2004.
Methods and Findings
There were 1.49 million births in Scotland over the study period, of which 5.8% were preterm. We found a percentage increase in crude rates of both spontaneous preterm birth per 1,000 singleton births (10.7%, p<0.01) and medically indicated preterm births (41.2%, p<0.01), which persisted when adjusted for maternal age at delivery. The greater proportion of spontaneous preterm births meant that the absolute increase in rates of preterm birth in each category were similar. Of specific maternal complications, essential and pregnancy-induced hypertension, pre-eclampsia, and placenta praevia played a decreasing role in preterm birth over the study period, with gestational and pre-existing diabetes playing an increasing role. There was a decline in stillbirth, neonatal, and extended perinatal mortality associated with preterm birth at all gestation over the study period but an increase in the rate of prolonged hospital stay for the neonate. Neonatal mortality improved in all subgroups, regardless of obstetric antecedent of preterm birth or gestational age. In the 28 wk and greater gestational groups we found a reduction in stillbirths and extended perinatal mortality for medically induced but not spontaneous preterm births (in the absence of maternal complications) although at the expense of a longer stay in neonatal intensive care. This improvement in stillbirth and neonatal mortality supports the decision making behind the 34% increase in elective/induced preterm birth in these women. Although improvements in neonatal outcomes overall are welcome, preterm birth still accounts for over 66% of singleton stillbirths, 65% of singleton neonatal deaths, and 67% of infants whose stay in the neonatal unit is “prolonged,” suggesting this condition remains a significant contributor to perinatal mortality and morbidity.
Conclusions
In our population, increases in spontaneous and medically induced preterm births have made equal contributions to the rising rate of preterm birth. Despite improvements in related perinatal mortality, preterm birth remains a major obstetric and neonatal problem, and its frequency is increasing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (gestation is the period during which a baby develops in its mother). Nowadays in the US, for example, more than half a million babies arrive earlier than expected every year (1 in 8 babies). Although improvements in the care of newborn babies (neonatal care) mean that preterm babies are more likely to survive than in the past, preterm birth remains the single biggest cause of infant death in many developed countries, and many preterm babies who survive have long-term health problems and disabilities, particularly those born before 32 weeks of gestation. Preterm births can be spontaneous or medically induced. At present, it impossible to predict which mothers will spontaneously deliver early and there is no effective way to prevent these preterm births; medically induced early labor is undertaken when either the unborn baby or mother would be at risk if the pregnancy continued to full term.
Why Was This Study Done?
Preterm birth rates need to be reduced, but before this can be done it is important to know how the causes of preterm birth, the numbers of preterm stillbirths, and the numbers of preterm babies who die at birth (neonatal deaths) or soon after (perinatal deaths) are changing with time. If, for example, the rise in preterm births is mainly due to an increase in medically induced labor and if this change in practice has reduced neonatal deaths, it would be unwise to try to reduce the preterm birth rate by discouraging medically induced preterm births. So far, data from the US and Latin America suggest that the increase in preterm births in these countries is solely due to increased rates of medically induced preterm births. However, in Europe and Australia, the rate of spontaneous preterm births also seems to be increasing. In this study, the researchers examine the trends over time and causes of preterm birth and of neonatal death and illness in Scotland over a 25-year period.
What Did the Researchers Do and Find?
By searching a Scottish database of linked maternity records and infant health and death records, the researchers identified 1.49 million singleton births that occurred between 1980 and 2004 of which nearly 90,000 were preterm births. Over the study period, the rates of spontaneous and of medically induced preterm births per 1,000 births increased by 10.7% and 41.2%, respectively, but because there were more spontaneous preterm births than medically induced preterm births, the absolute increase in the rates of each type of birth was similar. Several maternal complications including preeclampsia (a condition that causes high blood pressure) and placenta previa (covering of the opening of the cervix by the placenta) played a decreasing role in preterm births over the study period, whereas gestational and preexisting diabetes played an increasing role. Finally, there was a decline in stillbirths and in neonatal and perinatal deaths among preterm babies, although more babies remained in the hospital longer than 7 days after birth. More specifically, after 28 weeks of gestation, stillbirths and perinatal deaths decreased among medically induced preterm births but not among spontaneous preterm births.
What Do These Findings Mean?
These findings indicate that in Scotland between 1980 and 2004, increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births. Importantly, they also show that the increase in induced preterm births helped to reduce stillbirths and neonatal and perinatal deaths, a finding that supports the criteria that clinicians currently use to decide whether to induce an early birth. Nevertheless, preterm births still account for two-thirds of all stillbirths, neonatal deaths, and extended neonatal stays in hospital and thus cause considerable suffering and greatly increase the workload in neonatal units. The rates of such births consequently need to be reduced and, for Scotland at least, ways will have to be found to reduce the rates of both spontaneous and induced preterm births to achieve this goal while continuing to identify those sick babies who need to be delivered early to give them the best chance of survival.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000153
Tommys is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on maternal and infant health (in English and Spanish)
The US National Women's Health Information Center has detailed information about pregnancy, including a section on pregnancy complications
MedlinePlus provides links to other information on premature babies and to information on pregnancy (in English and Spanish)
doi:10.1371/journal.pmed.1000153
PMCID: PMC2740823  PMID: 19771156
14.  UK study of intrapartum care for low risk primigravidas: a survey of interventions 
STUDY OBJECTIVE: To determine the extent of intrapartum intervention received by primigravidas. DESIGN: Cross sectional survey of NHS hospitals in the UK. SETTING: One hundred and one randomly selected hospital maternity units. PARTICIPANTS: Forty consecutive primigravid women, judged to be at low risk at the start of labour, in each hospital. MAIN OUTCOME MEASURES: Seven groups of interventions or monitoring procedures were identified from the first, second, and third stages of labour: fetal monitoring, vaginal examinations, artificial rupture of membranes, augmentation of labour, pain relief, type of delivery, and episiotomy. Data were collected during 1993. MAIN RESULTS: Ninety eight hospitals took part in the study and data were collected on 3160 low risk primigravidas. Seventy four per cent of these women had continuous cardiotocography. The proportion of women having restrictive or invasive fetal monitoring showed appreciable geographical variation for both the first and second stages of labour. Using the criterion of a vaginal examination every four hours and allowing for the length of each woman's labour, 72% had more vaginal examinations than expected; there was a significant geographical variation in the number of women receiving more than five examinations. Fifty three per cent had artificial rupture of membranes; the procedure was performed over a wide range of cervical dilatations (0 cm-10 cm). Thirty eight per cent of labours were augmented, most commonly by intravenous syntocinon; the procedure showed significant geographical variation. Twenty eight per cent had a spinal block or epidural analgesia for the relief of pain; this intervention varied by geographical region only for the second stage of labour. Over one quarter of the women required instrumental delivery. Forty six per cent had an episiotomy; the frequency of this intervention varied substantially by region. There were no infant deaths. Twelve babies were recorded at birth as having a congenital anomaly. CONCLUSIONS: The rates of several interventions seem high for this low risk group and there was substantial geographical variation in the use of six interventions. Clinical trials are needed to evaluate the optimum criteria for using these interventions from which guidelines should be drawn up by local groups and the Royal College.
 
PMCID: PMC1756743  PMID: 9876360
15.  Assessment of perinatal outcome after sustained tocolysis in early labour (APOSTEL-II trial) 
Background
Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours.
Methods/Design
The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.
Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, β 0.2 at alpha 0.05).
Discussion
This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks.
Trial Registration
Clinical trial registration: , NTR 1336, date of registration: June 3rd 2008.
doi:10.1186/1471-2393-9-42
PMCID: PMC2754432  PMID: 19737426
16.  Preterm birth 
Clinical Evidence  2010;2010:1404.
Introduction
Preterm birth occurs in about 5% to 10% of all births in resource-rich countries, but in recent years the incidence seems to have increased in some countries, particularly in the USA. We found little reliable evidence for incidence in resource-poor countries. The rate in northwestern Ethiopia has been reported to vary from 11% to 22%, depending on the age group of mothers studied, and is highest in teenage mothers.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in women at high risk of preterm delivery? What are the effects of interventions to improve neonatal outcome after preterm rupture of membranes? What are the effects of treatments to stop contractions in preterm labour? What are the effects of elective compared with selective caesarean delivery for women in preterm labour? What are the effects of interventions to improve neonatal outcome in preterm delivery? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 58 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amnioinfusion for preterm rupture of membranes; antenatal corticosteroids; antibiotic treatment; bed rest; beta mimetics; calcium-channel blockers; elective caesarean; enhanced antenatal care programmes; magnesium sulphate; oxytocin receptor antagonists (atosiban); progesterone; prophylactic cervical cerclage; prostaglandin inhibitors (e.g., indometacin); selective caesarean; and thyrotropin-releasing hormone (TRH) (plus corticosteroids).
Key Points
Around 5% to 10% of all births in resource-rich countries occur before 37 weeks' gestation, leading to increased risks of neonatal and infant death, and of neurological disability in surviving infants.
Progestational agents such as progesterone and prophylactic cervical cerclage may reduce preterm birth when used in some high-risk women, but enhanced antenatal care programmes and bed rest have repeatedly shown to be ineffective or harmful. Prophylactic cervical cerclage may reduce preterm births in women with cervical changes or protruding membranes, but is unlikely to be effective — and may increase infection — in women with no cervical changes or with twin pregnancies.
A single course of antenatal corticosteroids reduces respiratory distress syndrome, intraventricular haemorrhage, and neonatal mortality compared with placebo in babies born before 37 weeks' gestation. Adding TRH to corticosteroids has not been shown to improve outcomes compared with corticosteroids alone, and increases the risk of adverse effects.
Antibiotics may prolong the pregnancy and reduce infection after premature rupture of the membranes, but are not beneficial when the membranes are intact.
Calcium-channel blockers may be effective at delaying labour compared with other tocolytics. Beta mimetics and magnesium sulphate do not prevent premature birth, and may increase fetal and maternal adverse effects compared with placebo. Oxytocin receptor antagonists (such as atosiban) and prostaglandin inhibitors (such as indometacin) may prevent preterm delivery.Most tocolytic therapies don't prevent perinatal mortality or morbidity, although they are usually underpowered to detect clinically significant differences in these outcomes.
Elective caesarean section increases maternal morbidity compared with selective caesarean section, but neonatal morbidity and mortality seem the same.
PMCID: PMC2907606
17.  Preterm birth 
Clinical Evidence  2011;2011:1404.
Introduction
Preterm birth occurs in about 5% to 10% of all births in resource-rich countries, but in recent years the incidence seems to have increased in some countries, particularly in the USA. We found little reliable evidence for incidence in resource-poor countries. The rate in northwestern Ethiopia has been reported to vary from 11% to 22%, depending on the age group of mothers studied, and is highest in teenage mothers.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in women at high risk of preterm delivery? What are the effects of interventions to improve neonatal outcome after preterm rupture of membranes? What are the effects of treatments to stop contractions in preterm labour? What are the effects of elective compared with selective caesarean delivery for women in preterm labour? What are the effects of interventions to improve neonatal outcome in preterm delivery? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 58 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amnioinfusion for preterm rupture of membranes, antenatal corticosteroids, antibiotic treatment, bed rest, beta-mimetics, calcium channel blockers, elective caesarean, enhanced antenatal care programmes, magnesium sulphate, oxytocin receptor antagonists (atosiban), progesterone, prophylactic cervical cerclage, prostaglandin inhibitors (e.g., indometacin), selective caesarean, and thyrotropin-releasing hormone (TRH) (plus corticosteroids).
Key Points
Around 5% to 10% of all births in resource-rich countries occur before 37 weeks' gestation, leading to increased risks of neonatal and infant death, and of neurological disability in surviving infants.
Progesterone may reduce preterm birth in women with prior preterm birth and a short cervix, but are unlikely to be beneficial and may even be harmful in women with multiple gestations.
Enhanced antenatal care programmes and bed rest have repeatedly been shown to be ineffective or harmful. Prophylactic cervical cerclage may reduce preterm births in women with cervical changes but is unlikely to be effective — and may increase infection — in women with no cervical changes or with twin pregnancies. We don't know how effective it is in women with protruding membranes.
A single course of antenatal corticosteroids reduces respiratory distress syndrome, intraventricular haemorrhage, and neonatal mortality compared with placebo in babies born before 37 weeks' gestation. Adding TRH to corticosteroids has not been shown to improve outcomes compared with corticosteroids alone, and increases the risk of adverse effects.
Antibiotics may prolong the pregnancy and reduce infection after premature rupture of the membranes, but are not beneficial when the membranes are intact.
It is unclear if amnioinfusion for preterm rupture of membranes reduces preterm birth or neonatal mortality, as we found few RCTs.
Calcium channel blockers may be effective at delaying labour compared with other tocolytics. Beta-mimetics and magnesium sulphate do not prevent premature birth, and may increase fetal and maternal adverse effects compared with placebo. Oxytocin receptor antagonists (such as atosiban) and prostaglandin inhibitors (such as indometacin) may prevent preterm delivery but we cannot be certain as we found few trials.Most tocolytic therapies don't prevent perinatal mortality or morbidity, although trials of these treatments are usually underpowered to detect clinically significant differences in these outcomes.
Elective caesarean section increases maternal morbidity compared with selective caesarean section, but rates of neonatal morbidity and mortality seem equivalent.
PMCID: PMC3217816  PMID: 21463540
18.  A randomised clinical trial on cardiotocography plus fetal blood sampling versus cardiotocography plus ST-analysis of the fetal electrocardiogram (STAN®) for intrapartum monitoring 
Background
Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive test results and without fetal blood sampling (FBS), it results in an increase in operative deliveries without improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two clinical trials have shown that a combination of CTG and ST-analysis of the fetal electrocardiogram (ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both trials FBS was still performed in the ST-analysis arm, and it is therefore still unknown if the observed results were indeed due to the ST-analysis or to the use of FBS in combination with ST-analysis.
Methods/Design
We aim to evaluate the effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in a multicentre randomised clinical trial setting. Secondary aims are: 1) to judge whether ST-analysis of fetal electrocardiogram can significantly decrease frequency of performance of FBS or even replace it; 2) perform a cost analysis to establish the economic impact of the two treatment options.
Women in labour with a gestational age ≥ 36 weeks and an indication for CTG-monitoring can be included in the trial.
Eligible women will be randomised for fetal surveillance with CTG and, if necessary, FBS or CTG combined with ST-analysis of the fetal ECG.
The primary outcome of the study is the incidence of serious metabolic acidosis (defined as pH < 7.05 and Bdecf > 12 mmol/L in the umbilical cord artery). Secondary outcome measures are: instrumental delivery, neonatal outcome (Apgar score, admission to a neonatal ward), incidence of performance of FBS in both arms and cost-effectiveness of both monitoring strategies across hospitals.
The analysis will follow the intention to treat principle. The incidence of metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic acidosis from 3.5% to 2.1 %, using a two-sided test with an alpha of 0.05 and a power of 0.80, in favour of CTG plus ST-analysis, about 5100 women have to be randomised. Furthermore, the cost-effectiveness of CTG and ST-analysis as compared to CTG and FBS will be studied.
Discussion
This study will provide data about the use of intrapartum ST-analysis with a strict protocol for performance of FBS to limit its incidence. We aim to clarify to what extent intrapartum ST-analysis can be used without the performance of FBS and in which cases FBS is still needed.
Trial Registration Number
ISRCTN95732366
doi:10.1186/1471-2393-7-13
PMCID: PMC1976105  PMID: 17655764
19.  Extended role for general practitioners in obstetrics? A medical audit. 
British Medical Journal  1979;1(6172):1199-1200.
A study was designed to evaluate provision of services, process of medical care, and outcome in four general-practitioner obstetric units in isolated areas (Berwick, Whitby, Guernsey, and Brecon). All units were equipped to induce labour; to perform instrumental vaginal delivery and selected breech deliveries; and to remove placentas manually. All had some fetal monitoring equipment. Caesarean sections could not be performed at Berwick and Whitby. Proportions of normal deliveries during 1976-7 varied from 75% to 93%. Perinatal mortality was acceptably low, as were transfer rates for neonates and mothers in labour. With specialist help and particular attention to training and broadening local doctors' experience of abnormal obstetrics, such units should be able to provide an excellent obstetric service.
PMCID: PMC1599360  PMID: 445003
20.  Concentration of fetal plasma and amniotic fluid interleukin-1 in pregnancies complicated by preterm prelabour amniorrhexis. 
Journal of Clinical Pathology  1995;48(4):368-371.
AIMS--To determine interleukin-1 beta (IL-1 beta) concentration in fetal and maternal plasma and amniotic fluid from pregnancies complicated by preterm prelabour amniorrhexis and to define the relation of this cytokine to intrauterine infection and the onset of labour. METHODS--Cross-sectional study of 23 pregnancies complicated by preterm prelabour amniorrhexis. Enzyme linked immunoassay was used to measure IL-1 beta concentration in fetal and maternal plasma and amniotic fluid. In each case, fetal blood and amniotic fluid were cultured for micro-organisms. RESULTS--In pregnancies with positive fetal blood and/or amniotic fluid cultures, plasma and amniotic fluid concentrations of IL-1 beta were higher and the interval between amniorrhexis and onset of labour was shorter than in the non-infected group. There were no significant associations between fetal plasma IL-1 beta and maternal plasma or amniotic fluid IL-1 beta concentrations, fetal leucocyte count or the interval between amniorrhexis and the onset of labour. CONCLUSIONS--These findings suggest that although intrauterine infection is associated with increased IL-1 beta concentrations in fetal plasma and amniotic fluid, there is no significant association between the concentration of IL-1 beta and the interval between amniorrhexis and the onset of labour.
PMCID: PMC502558  PMID: 7615859
21.  Re-Orientation of Clinical Research in Traumatic Brain Injury: Report of an International Workshop on Comparative Effectiveness Research 
Journal of Neurotrauma  2012;29(1):32-46.
Abstract
During the National Neurotrauma Symposium 2010, the DG Research of the European Commission and the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) organized a workshop on comparative effectiveness research (CER) in traumatic brain injury (TBI). This workshop reviewed existing approaches to improve outcomes of TBI patients. It had two main outcomes: First, it initiated a process of re-orientation of clinical research in TBI. Second, it provided ideas for a potential collaboration between the European Commission and the NIH/NINDS to stimulate research in TBI. Advances in provision of care for TBI patients have resulted from observational studies, guideline development, and meta-analyses of individual patient data. In contrast, randomized controlled trials have not led to any identifiable major advances. Rigorous protocols and tightly selected populations constrain generalizability. The workshop addressed additional research approaches, summarized the greatest unmet needs, and highlighted priorities for future research. The collection of high-quality clinical databases, associated with systems biology and CER, offers substantial opportunities. Systems biology aims to identify multiple factors contributing to a disease and addresses complex interactions. Effectiveness research aims to measure benefits and risks of systems of care and interventions in ordinary settings and broader populations. These approaches have great potential for TBI research. Although not new, they still need to be introduced to and accepted by TBI researchers as instruments for clinical research. As with therapeutic targets in individual patient management, so it is with research tools: one size does not fit all.
doi:10.1089/neu.2010.1599
PMCID: PMC3253305  PMID: 21545277
comparative effectiveness research; clinical research; clinical trials; methodology; systems biology; traumatic brain injury
22.  Assessment of Structural Connectivity in the Preterm Brain at Term Equivalent Age Using Diffusion MRI and T2 Relaxometry: A Network-Based Analysis 
PLoS ONE  2013;8(8):e68593.
Preterm birth is associated with a high prevalence of adverse neurodevelopmental outcome. Non-invasive techniques which can probe the neural correlates underpinning these deficits are required. This can be achieved by measuring the structural network of connections within the preterm infant's brain using diffusion MRI and tractography. We used diffusion MRI and T2 relaxometry to identify connections with altered white matter properties in preterm infants compared to term infants. Diffusion and T2 data were obtained from 9 term neonates and 18 preterm-born infants (born <32 weeks gestational age) at term equivalent age. Probabilistic tractography incorporating multiple fibre orientations was used in combination with the Johns Hopkins neonatal brain atlas to calculate the structural network of connections. Connections of altered diffusivity or T2, as well as their relationship with gestational age at birth and postmenstrual age at the time of MRI, were identified using the network based statistic framework. A total of 433 connections were assessed. FA was significantly reduced in 17, and T2 significantly increased in 18 connections in preterm infants, following correction for multiple comparisons. Cortical networks associated with affected connections mainly involved left frontal and temporal cortical areas: regions which are associated with working memory, verbal comprehension and higher cognitive function – deficits which are often observed later in children and adults born preterm. Gestational age at birth correlated with T2, but not diffusion in several connections. We found no association between diffusion or T2 and postmenstrual age at the time of MRI in preterm infants. This study demonstrates that alterations in the structural network of connections can be identified in preterm infants at term equivalent age, and that incorporation of non-diffusion measures such as T2 in the connectome framework provides complementary information for the assessment of brain development.
doi:10.1371/journal.pone.0068593
PMCID: PMC3737239  PMID: 23950872
23.  Immersion in water in labour and birth 
Background
Enthusiasts suggest that labouring in water and waterbirth increase maternal relaxation, reduce analgesia requirements and promote a midwifery model of care. Critics cite the risk of neonatal water inhalation and maternal/neonatal infection.
Objectives
To assess the evidence from randomised controlled trials about immersion in water during labour and waterbirth on maternal, fetal, neonatal and caregiver outcomes.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 June 2011) and reference lists of retrieved studies.
Selection criteria
Randomised controlled trials comparing immersion in any bath tub/pool with no immersion, or other non-pharmacological forms of pain management during labour and/or birth, in women during labour who were considered to be at low risk of complications, as defined by the researchers.
Data collection and analysis
We assessed trial eligibility and quality and extracted data independently. One review author entered data and the other checked for accuracy.
Main results
This review includes 12 trials (3243 women): eight related to just the first stage of labour: one to early versus late immersion in the first stage of labour; two to the first and second stages; and another to the second stage only. We identified no trials evaluating different baths/pools, or the management of third stage of labour.
Results for the first stage of labour showed there was a significant reduction in the epidural/spinal/paracervical analgesia/anaesthesia rate amongst women allocated to water immersion compared to controls (478/1254 versus 529/1245; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.82 to 0.99, six trials). There was also a reduction in duration of the first stage of labour (mean difference −32.4 minutes; 95% CI −58.7 to −6.13). There was no difference in assisted vaginal deliveries (RR 0.86; 95% CI 0.71 to 1.05, seven trials), caesarean sections (RR 1.21; 95% CI 0.87 to 1.68, eight trials), use of oxytocin infusion (RR 0.64; 95%CI 0.32 to 1.28,five trials), perineal trauma or maternal infection. There were no differences for Apgar score less than seven at five minutes (RR 1.58; 95% CI 0.63 to 3.93, five trials), neonatal unit admissions (RR 1.06; 95% CI 0.71 to 1.57, three trials), or neonatal infection rates (RR 2.00; 95% CI 0.50 to 7.94, five trials).
Of the three trials that compared water immersion during the second stage with no immersion, one trial showed a significantly higher level of satisfaction with the birth experience (RR 0.24; 95% CI 0.07 to 0.80).
A lack of data for some comparisons prevented robust conclusions. Further research is needed.
Authors’ conclusions
Evidence suggests that water immersion during the first stage of labour reduces the use of epidural/spinal analgesia and duration of the first stage of labour. There is limited information for other outcomes related to water use during the first and second stages of labour, due to intervention and outcome variability. There is no evidence of increased adverse effects to the fetus/neonate or woman from labouring in water or waterbirth. However, the studies are very variable and considerable heterogeneity was detected for some outcomes. Further research is needed.
doi:10.1002/14651858.CD000111.pub3
PMCID: PMC3982045  PMID: 19370552
24.  Characterising doctor-parent communication in counselling for impending preterm delivery 
Objective: To examine the counselling of women admitted to hospital in preterm labour. Such women and their partners are often asked to participate in difficult decisions including mode of delivery, fetal monitoring, and resuscitation.
Study design: Questionnaire based descriptive study.
Study setting: A tertiary level perinatal referral centre.
Patients: Forty nine women in preterm labour at 22–30 weeks gestation, admitted in two separate periods between March 1997 and May 1999.
Intervention and outcome measure: Within 24 hours of counselling, parents were asked to complete a questionnaire assessing recall of the management plan, desire for involvement in decision making, anxiety, and feelings of control over their health. A parallel questionnaire was completed by the clinicians.
Results: Parents and clinicians on recall agreed well about obstetric issues but poorly about neonatal issues. Overall 27% of parents felt: "I would prefer to have the doctors advise me, rather than asking me to decide". In 79% of cases, clinicians believed parents preferred advice rather than to make decisions, but in 45% of these, they misidentified those who wished to make their decisions. Anxiety levels for one third of the mothers were high, and associated with poorer concordance of recall between parents and clinicians.
Conclusions: Serious deficiencies exist in parent-clinician encounters during extremely preterm labour. Concordance between parents and clinicians is poor and anxiety very high. A quarter of parents appear to prefer to relinquish decision making autonomy, but clinicians cannot correctly identify this subgroup. Standardised counselling in the perinatal period, using formal decision aids, should be investigated.
doi:10.1136/fn.87.2.F113
PMCID: PMC1721446  PMID: 12193517
25.  Proceedings of the 2008 annual meeting of the Fetal Alcohol Spectrum Disorders Study Group 
Alcohol (Fayetteville, N.Y.)  2009;43(4):333-339.
The annual meeting of the Fetal Alcohol Spectrum Disorders Study Group (FASDSG) was held on June 28, 2008 in Washington DC, as a satellite to the Research Society on Alcoholism meeting. The FASDSG membership includes clinical, basic and social scientists, who meet to discuss recent advances and issues in FASD research. The main theme of the meeting was “Factors that Influence Brain and Behavioral Development: Implications for Prevention and Intervention.” Two keynote speakers, Dr. Stephen Suomi and Dr. Carl Keen addressed how early environment and nutrition may influence outcome following prenatal alcohol exposure. The final keynote speaker, Kathy Mitchell, addressed issues regarding the relationship between scientists and the families with children with FASD. Members of the FASDSG provided updates on new findings through brief (FASt) data reports, and national agency representative provided updates of activities and funding priorities. Presentations were also made by recipients of the Student Research Merit award and Rosett award.
doi:10.1016/j.alcohol.2009.04.004
PMCID: PMC2709793  PMID: 19560631
fetal alcohol syndrome; fetal alcohol spectrum disorders; teratology; ethanol; prenatal

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