Maternal and infant morbidity following birth before 27 weeks of gestation: a single centre study

Delivery at extreme preterm gestational ages (GA) [Formula: see text] weeks is challenging with limited evidence often focused only on neonatal outcomes. We reviewed management and short term maternal, fetal and neonatal outcomes of births for 132 women (22 + 0 to 26 + 6 weeks' GA) with a live fetus at admission to hospital and in labour or at planned emergency Caesarean section: 103 singleton and 29 (53 live fetuses) twin gestations. Thirty women (23%) had pre-existing medical problems, 110 (83%) had antenatal complications; only 17 (13%) women experienced neither. Major maternal labour and delivery complications affected 35 women (27%). 151 fetuses (97%) were exposed to antenatal steroids, 24 (15%) to tocolysis and 70 (45%) to magnesium sulphate. Delivery complications affected 11 fetuses, with 12 labour or delivery room deaths; survival to discharge was 75% (117/156), increasing with GA: 25% (1/4), 75% (18/24), 69% (29/42), 73% (33/45) and 88% (36/41) at 22, 23, 24, 25 and 26 weeks GA respectively (p = 0.024). No statistically important impact was seen from twin status, maternal illness or obstetric management. Even in a specialist perinatal unit antenatal and postnatal maternal complications are common in extreme preterm births, emphasising the need to include maternal as well as neonatal outcomes

Global Policy and Practice for Intrauterine Fetal Resuscitation During Fetal Surgery for Open Spina Bifida Repair

IMPORTANCE: Globally accepted recommendations suggest that a woman should be between 19 weeks and 25 weeks plus 6 days of pregnancy to be considered eligible for fetal closure of open spina bifida. A fetus requiring emergency delivery during surgery is therefore potentially considered viable and thus eligible for resuscitation. There is little evidence, however, to support how this scenario is addressed in clinical practice. OBJECTIVE: To explore current policy and practice for fetal resuscitation during fetal surgery for open spina bifida in centers undertaking fetal surgery. DESIGN, SETTING, AND PARTICIPANTS: An online survey was designed to identify current policies and practices in place to support fetal surgery for open spina bifida, exploring experiences and management of emergency fetal delivery and fetal death during surgery. The survey was emailed to 47 fetal surgery centers in 11 countries where fetal spina bifida repair is currently performed. These centers were identified through the literature, the International Society for Prenatal Diagnosis center repository, and an internet search. Centers were contacted between January 15 and May 31, 2021. Individuals volunteered participation through choosing to complete the survey. MAIN OUTCOMES AND MEASURES: The survey comprised 33 questions of mixed multiple choice, option selection, and open-ended formats. Questions explored policy and practice supporting fetal and neonatal resuscitation during fetal surgery for open spina bifida. RESULTS: esponses were obtained from 28 of 47 centers (60%) in 11 countries. Twenty cases of fetal resuscitation during fetal surgery during the last 5 years were reported across 10 centers. Four cases of emergency delivery during fetal surgery after maternal and/or fetal complications during the last 5 years were reported across 3 centers. Fewer than half the 28 centers (n = 12 [43%]) had policies in place to support practice in the event of either imminent fetal death (during or after fetal surgery) or the need for emergency fetal delivery during fetal surgery. Twenty of 24 centers (83%) reported preoperative parental counseling on the potential need for fetal resuscitation prior to fetal surgery. The gestational age at which centers would attempt neonatal resuscitation after emergency delivery varied from 22 weeks and 0 days to more than 28 weeks. CONCLUSIONS: In this global survey study of 28 fetal surgical centers, there was no standard practice about how fetal resuscitation or subsequent neonatal resuscitation was managed during open spina bifida repair. Further collaboration between professionals and parents is required to ensure sharing of information to support knowledge development in this area

Overcoming fears: a pathway to publishing for early career researchers

Purpose – The purpose of this paper is to present reflections of five early career researchers on the challenges of journal publishing and how to tackle them. Design/methodology/approach – The authors attended a participatory workshop on demystifying academic publications. Working individually and in groups the authors shared, discussed, analysed, visualised and ranked perceived challenges and opportunities concerning academic publishing. The authors then delved into the existing literature on the subject. Following their enhanced understanding of the area, the authors reflected on the experience and learnings. Findings – Personal confidence relating to the development of a scholarly identity was found to be a critical factor in the attitude towards journal publishing. Supervisory and peer support, accessibility to journal editors, as well as opportunities to reflect on the writing, publishing and peer review processes through participatory workshops and writing groups, were deemed more effective than formal and conventional guidance schemes. Research limitations/implications – This work adds to the available literature regarding the issue of academic publishing for PhD students and early career researchers. Originality/value – The paper contributes to a deeper understanding of issues surrounding publishing apprehension, by laying out thoughts that are seldom expressed

The Complementary Role of ToF-SIMS in the Assessment of Imiquimod Permeated into the Skin from a Microemulsion Dosage Form

The assessment of drug permeation into/across the skin is traditionally accomplished using Franz diffusion cells with subsequent analysis by conventional chromatographic methods such as HPLC and more recently using advanced imaging techniques. In this context, time   of flight-secondary ion mass spectrometry (ToF-SIMS) offers distinctive advantages in mapping drugs within skin with high sensitivity and chemical specificity without the need for fluorescent tags or radiolabels. The work in this paper uses the combination of conventional and advanced methods to evaluate imiquimod permeation into the skin. This approach provides complementary and detailed information regarding the permeated mass, the permeation depth and the spatial distribution and localisation of drugs within skin. Imiquimod is an immune modulator drug approved by the FDA for the treatment of superficial basal cell carcinoma (BCC) but not the nodular lesions. As other studies have reported that Aldara™ cream (imiquimod 5% w/w) has some limitations in the treatment of nodular BCC lesions due to the cream’s inability to deliver imiquimod into the deeper more invasive nodular lesions, an enhancement of imiquimod permeation is thought to be useful to overcome these limitations. Therefore, an attempt to improve delivery of imiquimod into the deeper skin layers using microemulsions was investigated. Imiquimod microemulsions were formulated and characterised in our previous work are now tested for skin permeation enhancement. However, the assessment of imiquimod permeation from the formulated microemulsions using HPLC and ToF-SIMS demonstrated a limited ability of the microemulsions to improve delivery of imiquimod over Aldara™ cream. This was attributed to the poor release of imiquimod from the microemulsion formulas due to the high affinity of imiquimod for the oil phase and the encapsulation of the oil droplets by the S/Co-S mixture. This is thought to be, the first time that ToF-SIMS has been used to assess permeation of imiquimod from a microemulsion dosage form

Insight into imiquimod skin permeation and increased delivery using microneedle pre-treatment

Basal cell carcinoma (BCC) is the most common skin cancer in humans. Topical treatment with imiquimod provides a non-invasive, self-administered treatment with relatively low treatment cost. Despite displaying excellent efficacy, imiquimod is only licensed by the FDA for superficial BCC. The current work employed HPLC and ToF-SIMS analysis to provide a novel assessment of imiquimod permeation from Aldara™ cream in skin depth and lateral distribution. Using Aldara™ cream and in vitro Franz cell studies with subsequent HPLC analysis, it is apparent that most of the topically applied imiquimod cream is left on the skin surface with more than 80% of the drug being recovered from skin wash. In addition, ToF-SIMS chemical imaging of recovered tape stripped skin samples illustrated significant detection of imiquimod signal over the entire skin area for the upper tape strips, whereas the deeper strips show large portions of the skin area without detected imiquimod. Given the limited permeation depth and non-uniform permeation observed at tape strips 6–18 when applied as a topical imiquimod cream, a permeation enhancement strategy utilising a skin pre-treatment with a microneedle device was investigated as a method to improve intradermal delivery. The recovered amount of imiquimod in tape strips and remaining skin determined by HPLC was approximately three times higher when Aldara™ was applied on microneedle pre-treated skin relative to intact skin. The ToF-SIMS ion images of the tape strips and cross-sections illustrated the existence of imiquimod in the microchannels which then laterally diffuses to peripheral epidermal strata. The current work demonstrates the first known attempt to enhance intradermal delivery of imiquimod using a microneedle device as well as underscoring the complementary role of ToF-SIMS analysis in chemically mapping imiquimod permeation into the skin with high sensitivity

Linifanib – a multi-targeted receptor tyrosine kinase inhibitor and a low molecular weight gelator

In this study we demonstrate that linifanib, a multi-targeted receptor tyrosine kinase inhibitor, with a key urea containing pharmacophore, self-assembles into a hydrogel in the presence of low amounts of solvent. We demonstrate the role of the urea functional group and that of fluorine substitution on the adjacent aromatic ring in promoting self-assembly. We have also shown that linifanib has superior mechanical strength to two structurally related analogues and hence increased potential for localisation at an injection site for drug delivery applications

Management of late-onset fetal growth restriction: pragmatic approach

OBJECTIVES: International guidelines recommend delivery from 37 weeks in small for gestational age (SGA) fetuses mostly because of stillbirth concerns. Differentiating SGA from late-onset fetal growth restriction (FGR) is challenged by the limited prospective evidence to guide management. We prospectively assessed a novel protocol that used ultrasound criteria to classify women with suspected late FGR into two groups: low-risk with expectant management until the expected date of delivery and high-risk with delivery soon after 37 weeks. Furthermore, we compared the outcome of this prospective cohort with a historical cohort of women similarly presenting with suspected late FGR, to evaluate the impact of implementation of the new protocol. METHODS: This was a prospective study in women with a singleton non-anomalous fetus at ≥32 weeks with any of the following inclusion criteria: estimated fetal weight (EFW) ≤10th centile, ≥50 centiles decrease of the abdominal circumference (AC) from previous scans, umbilical artery Doppler pulsatility index >95th centile or cerebroplacental ratio <5th centile. Women were stratified into low- or high-risk late FGR. Women in the low-risk group were delivered by 41 weeks unless meeting high-risk criteria for delivery later on, whereas women in the high-risk group (PAPP-A <0.4MoM, EFW <3rd centile, or EFW ≥3rd and ≤10th centile with AC drop or abnormal Dopplers) were delivered at 37 weeks. The primary outcome was adverse neonatal outcome including hypothermia, hypoglycemia, neonatal unit admission, jaundice requiring treatment, suspected infection, feeding difficulties, Apgar score <7 at 1 minute, hospital readmission and any of the severe adverse neonatal outcome (perinatal death, resuscitation using inotropes or mechanical ventilation, Apgar score <7 at 5 minutes, metabolic acidosis, sepsis, cerebral, cardiac or respiratory morbidity). Secondary outcomes were adverse maternal outcome (operative delivery for abnormal fetal heart rate) and severe adverse neonatal outcome. Women managed according with the new protocol were compared with a historical cohort where management was guided by individual clinician's expertise. RESULTS: Over 18 months (2018-2019), 321 women were included. Adverse neonatal outcome was significantly less common in low- (n=156) compared with high-risk fetus (n=165): 45 vs 57%; aOR, 0.6; 95% CI, 0.4-0.9; P=0.022. There was no significant difference in adverse maternal outcome (18% vs 24%; aOR, 0.7; 95% CI, 0.4-1.2; P=0.142) and severe adverse neonatal outcome (3.8% vs 8.5%; aOR: 0.5; 95% CI, 0.2-1.3; P=0.153) between low and high-risk group. Compared to women delivered prior to the implementation of the new protocol and classified retrospectively into low- and high-risk late FGR (n=323), there was a lower adverse neonatal outcome (45% vs 58%; aOR, 0.6; 95% CI, 0.4-0.9; P=0.026) in the low-risk late FGR clinic group. CONCLUSIONS: Appropriate risk classification to define management in low- and high-risk FGR groups was associated with reduced adverse neonatal outcome in the low-risk group. In clinical practice a policy of expectantly managing women with late-onset low-risk FGR pregnancies at term could improve neonatal and long-term development. Randomized controlled trials are needed to assess the effect of an evidence based conservative management protocol of late FGR on perinatal morbidity, mortality and long-term neurodevelopment

The impact of networks on clinical trials in the United Kingdom

The conduct of clinical trials in the UK has been affected by the recent introduction of managed clinical networks, clinical research networks and rigorous governance regulations. This commentary considers the challenges that these changes have posed for clinical triallists in the UK, based on experiences derived in the conduct of a multicentre neonatal clinical trial under the conditions that now prevail. We conclude that the considerable skills and knowledge that are now required to be an effective Principal Investigator should be recognised and that application processes, including issuing honorary contracts, should be simplified and centralised

Effects of gestational age at birth on cognitive performance : a function of cognitive workload demands

Objective: Cognitive deficits have been inconsistently described for late or moderately preterm children but are consistently found in very preterm children. This study investigates the association between cognitive workload demands of tasks and cognitive performance in relation to gestational age at birth. Methods: Data were collected as part of a prospective geographically defined whole-population study of neonatal at-risk children in Southern Bavaria. At 8;5 years, n = 1326 children (gestation range: 23–41 weeks) were assessed with the K-ABC and a Mathematics Test. Results: Cognitive scores of preterm children decreased as cognitive workload demands of tasks increased. The relationship between gestation and task workload was curvilinear and more pronounced the higher the cognitive workload: GA2 (quadratic term) on low cognitive workload: R2 = .02, p<0.001; moderate cognitive workload: R2 = .09, p<0.001; and high cognitive workload tasks: R2 = .14, p<0.001. Specifically, disproportionally lower scores were found for very (<32 weeks gestation) and moderately (32–33 weeks gestation) preterm children the higher the cognitive workload of the tasks. Early biological factors such as gestation and neonatal complications explained more of the variance in high (12.5%) compared with moderate (8.1%) and low cognitive workload tasks (1.7%). Conclusions: The cognitive workload model may help to explain variations of findings on the relationship of gestational age with cognitive performance in the literature. The findings have implications for routine cognitive follow-up, educational intervention, and basic research into neuro-plasticity and brain reorganization after preterm birth