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The objective of this review was to determine the timing of overall and cause-specific neonatal mortality and severe morbidity during the postnatal period (1-28 days).Despite significant focus on improving neonatal outcomes, many newborns continue to die or experience adverse health outcomes. While evidence on neonatal mortality and severe morbidity rates and causes are regularly updated, less is known on the specific timing of when they occur in the neonatal period.This review considered studies that reported on neonatal mortality daily in the first week; weekly in the first month; or day 1, days 2-7, and days 8-28. It also considered studies that reported on timing of severe neonatal morbidity. Studies that reported solely on preterm or high-risk infants were excluded, as these infants require specialized care. Due to available evidence, mixed samples were included (eg, both preterm and full-term infants), reflecting a neonatal population that may include both low-risk and high-risk infants.MEDLINE, Embase, Web of Science, and CINAHL were searched for published studies on December 20, 2019, and updated on May 10, 2021. Critical appraisal was undertaken by two independent reviewers using standardized critical appraisal instruments from JBI. Quantitative data were extracted from included studies independently by two reviewers using a study-specific data extraction form. All conflicts were solved through consensus or discussion with a third reviewer. Where possible, quantitative data were pooled in statistical meta-analysis. Where statistical pooling was not possible, findings were reported narratively.A total of 51 studies from 36 articles reported on relevant outcomes. Of the 48 studies that reported on timing of mortality, there were 6,845,490 live births and 47,551 neonatal deaths with timing known. Of the 34 studies that reported daily deaths in the first week, the highest proportion of deaths occurred on the first day (first 24 hours, 38.8%), followed by day 2 (24-48 hours, 12.3%). Considering weekly mortality within the first month (n = 16 studies), the first week was the highest mortality (71.7%). Based on data from 46 studies, the highest proportion of deaths occurred on day 1 (39.5%), followed closely by days 2-7 (36.8%), with the remainder occurring between days 8-28 (23.0%). In terms of causes, birth asphyxia accounted for the highest proportion of deaths on day 1 (68.1%), severe infection between days 2-7 (48.1%), and diarrhea between days 8-28 (62.7%). Due to heterogeneity, neonatal morbidity data were described narratively. The mean critical appraisal score of all studies was 84% (SD = 16%).Newborns experience high mortality throughout the entire postnatal period, with the highest mortality rate in the first week, particularly on the first day. Ensuring regular high-quality postnatal visits, particularly within the first week after birth, is paramount to reduce neonatal mortality and severe morbidity.

The purpose of this research was to explore parental perspectives on the impact of parent restrictions imposed in response to the COVID-19 pandemic across Canadian Neonatal Intensive Care Units (NICUs). A co-designed online survey was conducted targeting parents ( n = 235) of infants admitted to a Canadian NICU from March 1, 2020, until March 5, 2021. Parents completed the survey from 38 Canadian NICUs. Large variation in the severity of policies regarding parental presence was reported. Most respondents (68.9%) were classified as experiencing high restrictions, with one or no support people allowed in the NICU, and felt that policies were less easy to understand, felt less valued and respected, and found it more challenging to access medicine or health care. Parents reported gaps in care related to self-care, accessibility, and mental health outcomes. There is significant variation in parental restrictions implemented across Canadian NICUs. National guidelines are needed to support consistent and equitable care practices.

Background In response to the COVID-19 pandemic, family presence restrictions in neonatal intensive care units (NICU) were enacted to limit disease transmission. This has resulted in communication challenges, negatively impacting family integrated care. Aim To develop clinical care pathways to ensure optimal neonatal care to support families in response to parental presence restrictions imposed during the COVID-19 pandemic. Methods An agile, co-design process utilizing expert consensus of a large interdisciplinary team and focus groups and semi-structured interviews with families and HCPs were used to co-design clinical virtual care pathways. Results Three clinical virtual care pathways were co-designed: (1) building and maintaining relationships between family and healthcare providers; (2) awareness of resources; and (3) standardized COVID-19 messaging. Modifications were made to optimize uptake and utilization in the clinical areas. Conclusion Clinical care virtual pathways were successfully co-designed to meet these needs to ensure more equitable family centered care.

Background Presence in the neonatal intensive care unit (NICU) is a vital step for caregivers initiating involvement, such as skin-to-skin contact, holding or singing/reading to their newborn. Little is known about caregiver presence and involvement in Canadian NICU's context by caregiver type (mother, father, other), and the association between maternal presence and key maternal and newborn characteristics. Purpose The primary objective was to examine the presence and involvement of family caregivers in the NICU. The secondary objective was to examine the relationship between maternal presence and maternal and newborn characteristics. Design and methods A prospective observational cohort study in an open bay setting of an Eastern Canadian NICU. Presence (physically present at the newborn's bedside) and involvement (e.g., skin-to-skin, singing/reading) were tracked daily by families in the NICU until discharge. Demographic information was also collected. Results Participants included 142 mothers and their newborns. Mothers were present 8.7 h/day, fathers were present 4.1 h/day, and other caregivers were present 1.8 h/day in the NICU in the first 34 days. Mothers were involved in care activities 50% of the time they were present in the NICU, whereas fathers and other caregivers were spending 20% and 6% of their time respectively. Regression identified maternal age, distance to home, parity, birthweight, and length of stay to be statistically significant variables related to maternal presence. Conclusions There is variation in presence and involvement by caregiver type. Targeted interventions to maintain and increase mothers, fathers and other caregivers' presence and involvement in care throughout their stay in the NICU are recommended.

Background Therapeutic hypothermia is standard of care for babies with moderate to severe hypoxic–ischaemic encephalopathy. There is limited evidence to inform provision of nutrition during hypothermia. Objectives To assess the association during therapeutic hypothermia between (1) enteral feeding and outcomes, such as necrotising enterocolitis and (2) parenteral nutrition and outcomes, such as late-onset bloodstream infection. Design A retrospective cohort study using data held in the National Neonatal Research Database and applying propensity score methodology to form matched groups for analysis. Setting NHS neonatal units in England, Wales and Scotland. Participants Babies born at ≥ 36 gestational weeks between 1 January 2010 and 31 December 2017 who received therapeutic hypothermia for 72 hours or who died during treatment. Interventions Enteral feeding analysis – babies who were enterally fed during therapeutic hypothermia (intervention) compared with babies who received no enteral feeds during therapeutic hypothermia (control). Parenteral nutrition analysis – babies who received parenteral nutrition during therapeutic hypothermia (intervention) compared with babies who received no parenteral nutrition during therapeutic hypothermia (control). Outcome measures Primary outcomes were severe and pragmatically defined necrotising enterocolitis (enteral feeding analysis) and late-onset bloodstream infection (parenteral nutrition analysis). Secondary outcomes were survival at neonatal discharge, length of neonatal stay, breastfeeding at discharge, onset of breastfeeding, time to first maternal breast milk, hypoglycaemia, number of days with a central line in situ, duration of parenteral nutrition, time to full enteral feeds and growth. Results A total of 6030 babies received therapeutic hypothermia. Thirty-one per cent of babies received enteral feeds and 25% received parenteral nutrition. Seven babies (0.1%) were diagnosed with severe necrotising enterocolitis, and further comparative analyses were not conducted on this outcome. A total of 3236 babies were included in the matched enteral feeding analysis. Pragmatically defined necrotising enterocolitis was rare in both groups (0.5% vs. 1.1%) and was lower in babies who were fed during hypothermia (rate difference –0.5%, 95% confidence interval –1.0% to –0.1%; p = 0.03). Higher survival to discharge (96.0% vs. 90.8%, rate difference 5.2%, 95% confidence interval 3.9% to 6.6%; p p p = 0.03). Survival was lower in babies who did not receive parenteral nutrition (90.0% vs. 93.1%, rate difference 3.1%, 95% confidence interval 1.5% to 4.7%; p Limitations Propensity score methodology can address imbalances in observed confounders only. Residual confounding by unmeasured or poorly recorded variables cannot be ruled out. We did not analyse by type or volume of enteral or parenteral nutrition. Conclusions Necrotising enterocolitis is rare in babies receiving therapeutic hypothermia, and the introduction of enteral feeding is associated with a lower risk of pragmatically defined necrotising enterocolitis and other beneficial outcomes, including rates of higher survival and breastfeeding at discharge. Receipt of parenteral nutrition during therapeutic hypothermia is associated with a higher rate of late-onset infection but lower mortality. These results support introduction of enteral feeding during therapeutic hypothermia. Future work Randomised trials to assess parenteral nutrition during therapeutic hypothermia. Trial registration Current Controlled Trials ISRCTN474042962. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 36. See the NIHR Journals Library website for further project information.

The objective of this review was to determine the timing of overall and cause-specific maternal mortality and severe morbidity during the postpartum period.Many women continue to die or experience adverse health outcomes in the postpartum period; however, limited work has explored the timing of when women die or present complications during this period globally.This review considered studies that reported on women after birth up to 6 weeks postpartum and included data on mortality and/or morbidity on the first day, days 2-7, and days 8-42. Studies that reported solely on high-risk women (eg, those with antenatal or intrapartum complications) were excluded, but mixed population samples were included (eg, low-risk and high-risk women).MEDLINE, Embase, Web of Science, and CINAHL were searched for published studies on December 20, 2019, and searches were updated on May 11, 2021. Critical appraisal was undertaken by 2 independent reviewers using standardized critical appraisal instruments from JBI. Quantitative data were extracted from included studies independently by at least 2 reviewers using a study-specific data extraction form. Quantitative data were pooled, where possible. Identified studies were used to obtain the summary estimate (proportion) for each time point. Maternal mortality was calculated as the maternal deaths during a given period over the total number of maternal deaths known during the postpartum period. For cause-specific analysis, number of deaths due to a specific cause was the numerator, while the total number of women who died due to the same cause in that period was the denominator. Random effects models were run to pool incidence proportion for relative risk of overall maternal deaths. Subgroup analysis was conducted according to country income classification and by date (ie, data collection before or after 2010). Where statistical pooling was not possible, the findings were reported narratively.A total of 32 studies reported on maternal outcomes from 17 reports, all reporting on mixed populations. Most maternal deaths occurred on the first day (48.9%), with 24.5% of deaths occurring between days 2 and 7, and 24.9% occurring between days 8 and 42. Maternal mortality due to postpartum hemorrhage and embolism occurred predominantly on the first day (79.1% and 58.2%, respectively). Most deaths due to postpartum eclampsia and hypertensive disorders occurred within the first week (44.3% on day 1 and 37.1% on days 2-7). Most deaths due to infection occurred between days 8 and 42 (61.3%). Due to heterogeneity, maternal morbidity data are described narratively, with morbidity predominantly occurring within the first 2 weeks. The mean critical appraisal score across all included studies was 85.9% (standard deviation = 13.6%).Women experience mortality throughout the entire postpartum period, with the highest mortality rate on the first day. Access to high-quality care during the postpartum period, including enhanced frequency and quality of postpartum assessments during the first 42 days after birth, is essential to improving maternal outcomes and to continue reducing maternal mortality and morbidity worldwide.PROSPERO CRD42020187341.

ObjectiveTo determine the impact of supplemental bovine lactoferrin on the gut microbiome and metabolome of preterm infants.DesignCohort study nested within a randomised controlled trial (RCT). Infants across different trial arms were matched on several clinical variables. Bacteria and metabolite compositions of longitudinal stool and urine samples were analysed to investigate the impact of lactoferrin supplementation.SettingThirteen UK hospitals participating in a RCT of lactoferrin.Patients479 infants born Results10 990 stool and 22 341 urine samples were collected. Analyses of gut microbiome (1304 stools, 201 infants), metabolites (171 stools, 83 infants; 225 urines, 90 infants) and volatile organic compounds (314 stools, 117 infants) were performed. Gut microbiome Shannon diversity at 34 weeks corrected age was not significantly different between infants in the lactoferrin (mean=1.24) or placebo (mean=1.06) groups (p=0.11). Lactoferrin receipt explained less than 1% variance in microbiome compositions between groups. Metabolomic analysis identified six discriminative features between trial groups. Hospital site (16%) and postnatal age (6%) explained the greatest variation in microbiome composition.ConclusionsThis multiomic study identified minimal impacts of lactoferrin but much larger impacts of hospital site and postnatal age. This may be due to the specific lactoferrin product used, but more likely supports the findings of the RCT in which this study was nested, which showed no impact of lactoferrin on reducing rates of sepsis. Multisite mechanistic studies nested within RCTs are feasible and help inform trial interpretation and future trial design.

BackgroundParenteral nutrition is commonly administered during therapeutic hypothermia. Randomised trials in critically ill children indicate that parenteral nutrition may be harmful.ObjectiveTo examine the association between parenteral nutrition during therapeutic hypothermia and clinically important outcomes.DesignRetrospective, population-based cohort study using the National Neonatal Research Database; propensity scores were used to create matched groups for comparison.SettingNational Health Service neonatal units in England, Scotland and Wales.Participants6030 term and near-term babies, born 1/1/2010 and 31/12/2017, who received therapeutic hypothermia; 2480 babies in the matched analysis.ExposureWe compared babies that received any parenteral nutrition during therapeutic hypothermia with babies that did not.Main outcome measuresPrimary outcome: blood culture confirmed late-onset infection; secondary outcomes: treatment for late onset infection, necrotising enterocolitis, survival, length of stay, measures of breast feeding, hypoglycaemia, central line days, time to full enteral feeds, discharge weight.Results1475/6030 babies (25%) received parenteral nutrition. In comparative matched analyses, the rate of culture positive late onset infection was higher in babies that received parenteral nutrition (0.3% vs 0.9%; difference 0.6; 95% CI 0.1, 1.2; p=0.03), but treatment for presumed infection was not (difference 0.8%, 95% CI −2.1 to 3.6, p=0.61). Survival was higher in babies that received parenteral nutrition (93.1% vs 90.0%; rate difference 3.1, 95% CI 1.5, 4.7; pConclusionsReceipt of parenteral nutrition during therapeutic hypothermia is associated with higher late-onset infection but lower mortality. This finding may be explained by residual confounding. Research should address the risks and benefits of parenteral nutrition in this population.

BackgroundThe provision of neonatal care is variable and commonly lacks adequate evidence base; strategic development of methodologically robust clinical trials is needed to improve outcomes and maximise research resources. Historically, neonatal research topics have been selected by researchers; prioritisation processes involving wider stakeholder groups have generally identified research themes rather than specific questions amenable to interventional trials.ObjectiveTo involve stakeholders including parents, healthcare professionals and researchers to identify and prioritise research questions suitable for answering in neonatal interventional trials in the UK.DesignResearch questions were submitted by stakeholders in population, intervention, comparison, outcome format through an online platform. Questions were reviewed by a representative steering group; duplicates and previously answered questions were removed. Eligible questions were entered into a three-round online Delphi survey for prioritisation by all stakeholder groups.ParticipantsOne hundred and eight respondents submitted research questions for consideration; 144 participants completed round one of the Delphi survey, 106 completed all three rounds.ResultsTwo hundred and sixty-five research questions were submitted and after steering group review, 186 entered into the Delphi survey. The top five ranked research questions related to breast milk fortification, intact cord resuscitation, timing of surgical intervention in necrotising enterocolitis, therapeutic hypothermia for mild hypoxic ischaemic encephalopathy and non-invasive respiratory support.ConclusionsWe have identified and prioritised research questions suitable for practice-changing interventional trials in neonatal medicine in the UK at the present time. Trials targeting these uncertainties have potential to reduce research waste and improve neonatal care.

ImportanceThere is wide variability in the use of prophylactic cyclooxygenase inhibitor (COX-I) drugs to prevent morbidity and mortality in preterm infants. Parents of preterm infants are rarely involved in this decision-making process.ObjectiveTo explore the health-related values and preferences of adults who were preterm infants and families of preterm infants concerning the prophylactic use of indomethacin, ibuprofen, and acetaminophen initiated within the first 24 hours after birth.Design, Setting, and ParticipantsThis cross-sectional study used direct choice experiments conducted in 2 phases of virtual video-conferenced interviews between March 3, 2021, and February 10, 2022: (1) a pilot feasibility study and (2) a formal study of values and preferences, using a predefined convenience sample. Participants included adults born very preterm (gestational age Main Outcomes and MeasuresRelative importance of clinical outcomes, willingness to use each of the COX-Is when presented as the only option, preference for using prophylactic hydrocortisone vs indomethacin, willingness to use any of the COX-Is when all 3 options are available, and relative importance of having family values and preferences included in decision-making.ResultsOf 44 participants enrolled, 40 were included in the formal study (31 parents and 9 adults born preterm). The median gestational age of the participant or the participant’s child at birth was 26.0 (IQR, 25.0-28.8) weeks. Death (median score, 100 [IQR, 100-100]) and severe intraventricular hemorrhage (IVH) (median score, 90.0 [IQR, 80.0-100]) were rated as the 2 most critical outcomes. Based on direct choice experiments, most participants were willing to consider prophylactic indomethacin (36 [90.0%]) or ibuprofen (34 [85.0%]), but not acetaminophen (4 [10.0%]) when offered as the only option. Among participants who initially chose indomethacin (n = 36), if prophylactic hydrocortisone was offered as a potential therapy with the caveat that both cannot be used simultaneously, only 12 of 36 (33.3%) preferred to remain with indomethacin. Variability in preference was noted when all 3 COX-I options were available, indomethacin (19 [47.5%]) being the most preferred option followed by ibuprofen (16 [40.0%]), while the remainder opted for no prophylaxis (5 [12.5%]).Conclusions and RelevanceThe findings of this cross-sectional study of former preterm infants and parents of preterm infants suggest that there was minimal variability in how participants valued the main outcomes, with death and severe IVH being rated as the 2 most important undesirable outcomes. While indomethacin was the most preferred form of prophylaxis, variability was noted in the choice of COX-I interventions when participants were presented with the benefits and harms of each drug.

BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Cyclooxygenase inhibitors (COX‐I) may prevent PDA‐related complications. Controversy exists on which COX‐I drug is the most effective and has the best safety profile in preterm infants. OBJECTIVES: To compare the effectiveness and safety of prophylactic COX‐I drugs and 'no COXI prophylaxis' in preterm infants using a Bayesian network meta‐analysis (NMA). SEARCH METHODS: Searches of Cochrane CENTRAL via Wiley, OVID MEDLINE and Embase via Elsevier were conducted on 9 December 2021. We conducted independent searches of clinical trial registries and conference abstracts; and scanned the reference lists of included trials and related systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled preterm or low birth weight infants within the first 72 hours of birth without a prior clinical or echocardiographic diagnosis of PDA and compared prophylactic administration of indomethacin or ibuprofen or acetaminophen versus each other, placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. We used the GRADE NMA approach to assess the certainty of evidence derived from the NMA for the following outcomes: severe intraventricular haemorrhage (IVH), mortality, surgical or interventional PDA closure, necrotizing enterocolitis (NEC), gastrointestinal perforation, chronic lung disease (CLD) and cerebral palsy (CP). MAIN RESULTS: We included 28 RCTs (3999 preterm infants). Nineteen RCTs (n = 2877) compared prophylactic indomethacin versus placebo/no treatment, 7 RCTs (n = 914) compared prophylactic ibuprofen versus placebo/no treatment and 2 RCTs (n = 208) compared prophylactic acetaminophen versus placebo/no treatment. Nine RCTs were judged to have high risk of bias in one or more domains.We identified two ongoing trials on prophylactic acetaminophen. Bayesian random‐effects NMA demonstrated that prophylactic indomethacin probably led to a small reduction in severe IVH (network RR 0.66, 95% Credible Intervals [CrI] 0.49 to 0.87; absolute risk difference [ARD] 43 fewer [95% CrI, 65 fewer to 16 fewer] per 1000; median rank 2, 95% CrI 1‐3; moderate‐certainty), a moderate reduction in mortality (network RR 0.85, 95% CrI 0.64 to 1.1; ARD 24 fewer [95% CrI, 58 fewer to 16 more] per 1000; median rank 2, 95% CrI 1‐4; moderate‐certainty) and surgical PDA closure (network RR 0.40, 95% CrI 0.14 to 0.66; ARD 52 fewer [95% CrI, 75 fewer to 30 fewer] per 1000; median rank 2, 95% CrI 1‐2; moderate‐certainty) compared to placebo. Prophylactic indomethacin resulted in trivial difference in NEC (network RR 0.76, 95% CrI 0.35 to 1.2; ARD 16 fewer [95% CrI, 42 fewer to 13 more] per 1000; median rank 2, 95% CrI 1‐3; high‐certainty), gastrointestinal perforation (network RR 0.92, 95% CrI 0.11 to 3.9; ARD 4 fewer [95% CrI, 42 fewer to 137 more] per 1000; median rank 1, 95% CrI 1‐3; moderate‐certainty) or CP (network RR 0.97, 95% CrI 0.44 to 2.1; ARD 3 fewer [95% CrI, 62 fewer to 121 more] per 1000; median rank 2, 95% CrI 1‐3; low‐certainty) and may result in a small increase in CLD (network RR 1.10, 95% CrI 0.93 to 1.3; ARD 36 more [95% CrI, 25 fewer to 108 more] per 1000; median rank 3, 95% CrI 1‐3; low‐certainty). Prophylactic ibuprofen probably led to a small reduction in severe IVH (network RR 0.69, 95% CrI 0.41 to 1.14; ARD 39 fewer [95% CrI, 75 fewer to 18 more] per 1000; median rank 2, 95% CrI 1‐4; moderate‐certainty) and moderate reduction in surgical PDA closure (network RR 0.24, 95% CrI 0.06 to 0.64; ARD 66 fewer [95% CrI, from 82 fewer to 31 fewer] per 1000; median rank 1, 95% CrI 1‐2; moderate‐certainty) compared to placebo. Prophylactic ibuprofen may result in moderate reduction in mortality (network RR 0.83, 95% CrI 0.57 to 1.2; ARD 27 fewer [95% CrI, from 69 fewer to 32 more] per 1000; median rank 2, 95% CrI 1‐4; low‐certainty) and leads to trivial difference in NEC (network RR 0.73, 95% CrI 0.31 to 1.4; ARD 18 fewer [95% CrI, from 45 fewer to 26 more] per 1000; median rank 1, 95% CrI 1‐3; high‐certainty), or CLD (network RR 1.00, 95% CrI 0.83 to 1.3; ARD 0 fewer [95% CrI, from 61 fewer to 108 more] per 1000; median rank 2, 95% CrI 1‐3; low‐certainty). The evidence is very uncertain on effect of ibuprofen on gastrointestinal perforation (network RR 2.6, 95% CrI 0.42 to 20.0; ARD 76 more [95% CrI, from 27 fewer to 897 more] per 1000; median rank 3, 95% CrI 1‐3; very low‐certainty). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (network RR 1.17, 95% CrI 0.04 to 55.2; ARD 22 more [95% CrI, from 122 fewer to 1000 more] per 1000; median rank 4, 95% CrI 1‐4; very low‐certainty), mortality (network RR 0.49, 95% CrI 0.16 to 1.4; ARD 82 fewer [95% CrI, from 135 fewer to 64 more] per 1000; median rank 1, 95% CrI 1‐4; very low‐certainty), or CP (network RR 0.36, 95% CrI 0.01 to 6.3; ARD 70 fewer [95% CrI, from 109 fewer to 583 more] per 1000; median rank 1, 95% CrI 1‐3; very low‐certainty). In summary, based on ranking statistics, both indomethacin and ibuprofen were equally effective (median ranks 2 respectively) in reducing severe IVH and mortality. Ibuprofen (median rank 1) was more effective than indomethacin in reducing surgical PDA ligation (median rank 2). However, no statistically‐significant differences were observed between the COX‐I drugs for any of the relevant outcomes. AUTHORS' CONCLUSIONS: Prophylactic indomethacin probably results in a small reduction in severe IVH and moderate reduction in mortality and surgical PDA closure (moderate‐certainty), may result in a small increase in CLD (low‐certainty) and results in trivial differences in NEC (high‐certainty), gastrointestinal perforation (moderate‐certainty) and cerebral palsy (low‐certainty). Prophylactic ibuprofen probably results in a small reduction in severe IVH and moderate reduction in surgical PDA closure (moderate‐certainty), may result in a moderate reduction in mortality (low‐certainty) and trivial differences in CLD (low‐certainty) and NEC (high‐certainty). The evidence is very uncertain about the effect of acetaminophen on any of the clinically‐relevant outcomes.

Mechanical ventilation is an uncomfortable and potentially painful intervention. Opioids, such as morphine and fentanyl, are used for analgesia and sedation but there is uncertainty whether they reduce pain in mechanically ventilated infants. Moreover, there may be short-term and long-term adverse consequences such as respiratory depression leading to prolonged mechanical ventilation and detrimental long-term neurodevelopmental effects. Despite this, opioids are widely used, possibly due to a lack of alternatives.Dexmedetomidine, a highly selective alpha-2-adrenergic agonist with analgesic and sedative effects, currently approved for adults, has come into use in newborn infants. It provides analgesia and simulates natural sleep with maintenance of spontaneous breathing and upper airway tone. Although data on pharmacokinetics–pharmacodynamics in preterm infants are scant, observational studies report that using dexmedetomidine in conjunction with opioids/benzodiazepines or on its own can reduce the cumulative exposure to opioids/benzodiazepines. As it does not cause respiratory depression, dexmedetomidine could enable quicker weaning and extubation. Dexmedetomidine has also been suggested as an adjunct to therapeutic hypothermia in hypoxic ischaemic encephalopathy and others have used it during painful procedures and surgery. Dexmedetomidine infusion can cause bradycardia and hypotension although most report clinically insignificant effects.The increasing number of publications of observational studies and clinical use demonstrates that dexmedetomidine is being used in newborn infants but data on safety and efficacy are scant and not of high quality. Importantly, there are no data on long-term neurodevelopmental impact on preterm or term-born infants. The acceptance of dexmedetomidine in routine clinical practice must be preceded by clinical evidence. We need adequately powered and well-designed randomised controlled trials investigating whether dexmedetomidine alone or with opioids/benzodiazepines in infants on mechanical ventilation reduces the need for opioids/benzodiazepine and improves neurodevelopment at 24 months and later as compared with the use of opioids/benzodiazepines alone.

Background Clinical trials show that antimicrobial-impregnated central venous catheters reduce catheter-related bloodstream infection in adults and children receiving intensive care, but there is insufficient evidence for use in newborn babies. Objectives The objectives were (1) to determine clinical effectiveness by conducting a randomised controlled trial comparing antimicrobial-impregnated peripherally inserted central venous catheters with standard peripherally inserted central venous catheters for reducing bloodstream or cerebrospinal fluid infections (referred to as bloodstream infections); (2) to conduct an economic evaluation of the costs, cost-effectiveness and value of conducting additional research; and (3) to conduct a generalisability analysis of trial findings to neonatal care in the NHS. Design Three separate studies were undertaken, each addressing one of the three objectives. (1) This was a multicentre, open-label, pragmatic randomised controlled trial; (2) an analysis was undertaken of hospital care costs, lifetime cost-effectiveness and value of information from an NHS perspective; and (3) this was a retrospective cohort study of bloodstream infection rates in neonatal units in England. Setting The randomised controlled trial was conducted in 18 neonatal intensive care units in England. Participants Participants were babies who required a peripherally inserted central venous catheter (of 1 French gauge in size). Interventions The interventions were an antimicrobial-impregnated peripherally inserted central venous catheter (coated with rifampicin–miconazole) or a standard peripherally inserted central venous catheter, allocated randomly (1 : 1) using web randomisation. Main outcome measure Study 1 – time to first bloodstream infection, sampled between 24 hours after randomisation and 48 hours after peripherally inserted central venous catheter removal. Study 2 – cost-effectiveness of the antimicrobial-impregnated peripherally inserted central venous catheter compared with the standard peripherally inserted central venous catheters. Study 3 – risk-adjusted bloodstream rates in the trial compared with those in neonatal units in England. For study 3, the data used were as follows: (1) case report forms and linked death registrations; (2) case report forms and linked death registrations linked to administrative health records with 6-month follow-up; and (3) neonatal health records linked to infection surveillance data. Results Study 1, clinical effectiveness – 861 babies were randomised (antimicrobial-impregnated peripherally inserted central venous catheter, n = 430; standard peripherally inserted central venous catheter, n = 431). Bloodstream infections occurred in 46 babies (10.7%) randomised to antimicrobial-impregnated peripherally inserted central venous catheters and in 44 (10.2%) babies randomised to standard peripherally inserted central venous catheters. No difference in time to bloodstream infection was detected (hazard ratio 1.11, 95% confidence interval 0.73 to 1.67; p = 0.63). Secondary outcomes of rifampicin resistance in positive blood/cerebrospinal fluid cultures, mortality, clinical outcomes at neonatal unit discharge and time to peripherally inserted central venous catheter removal were similar in both groups. Rifampicin resistance in positive peripherally inserted central venous catheter tip cultures was higher in the antimicrobial-impregnated peripherally inserted central venous catheter group (relative risk 3.51, 95% confidence interval 1.16 to 10.57; p = 0.02) than in the standard peripherally inserted central venous catheter group. Adverse events were similar in both groups. Study 2, economic evaluation – the mean cost of babies’ hospital care was £83,473. Antimicrobial-impregnated peripherally inserted central venous catheters were not cost-effective. Given the increased price, compared with standard peripherally inserted central venous catheters, the minimum reduction in risk of bloodstream infection for antimicrobial-impregnated peripherally inserted central venous catheters to be cost-effective was 3% and 15% for babies born at 23–27 and 28–32 weeks’ gestation, respectively. Study 3, generalisability analysis – risk-adjusted bloodstream infection rates per 1000 peripherally inserted central venous catheter days were similar among babies in the trial and in all neonatal units. Of all bloodstream infections in babies receiving intensive or high-dependency care in neonatal units, 46% occurred during peripherally inserted central venous catheter days. Limitations The trial was open label as antimicrobial-impregnated and standard peripherally inserted central venous catheters are different colours. There was insufficient power to determine differences in rifampicin resistance. Conclusions No evidence of benefit or harm was found of peripherally inserted central venous catheters impregnated with rifampicin–miconazole during neonatal care. Interventions with small effects on bloodstream infections could be cost-effective over a child’s life course. Findings were generalisable to neonatal units in England. Future research should focus on other types of antimicrobial impregnation of peripherally inserted central venous catheters and alternative approaches for preventing bloodstream infections in neonatal care. Trial registration Current Controlled Trials ISRCTN81931394. Funding This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 57. See the NIHR Journals Library website for further project information.

Background Routine measurement of gastric residual volume to guide feeding is widespread in neonatal units but not supported by high-quality evidence. Outcome selection is critical to trial design. Objective To determine optimal outcome measures for a trial of not routinely measuring gastric residual volume in neonatal care. Design A focused literature review, parent interviews, modified two-round Delphi survey and stakeholder consensus meeting. Participants Sixty-one neonatal healthcare professionals participated in an eDelphi survey; 17 parents were interviewed. 19 parents and neonatal healthcare professionals took part in the consensus meeting. Results Literature review generated 14 outcomes, and parent interviews contributed eight additional outcomes; these 22 outcomes were then ranked by 74 healthcare professionals in the first Delphi round where four further outcomes were proposed; 26 outcomes were ranked in the second round by 61 healthcare professionals. Five outcomes were categorised as ‘consensus in’, and no outcomes were voted ‘consensus out’. ‘No consensus’ outcomes were discussed and voted on in a face-to-face meeting by 19 participants, where four were voted ‘consensus in’. The final nine consensus outcomes were: mortality, necrotising enterocolitis, time to full enteral feeds, duration of parenteral nutrition, time feeds stopped per 24 hours, healthcare-associated infection; catheter-associated bloodstream infection, change in weight between birth and neonatal discharge and pneumonia due to milk aspiration. Conclusions and relevance We have identified outcomes for a trial of no routine measurement of gastric residual volume to guide feeding in neonatal care. This outcome set will ensure outcomes are important to healthcare professionals and parents.

Background Early reports of COVID-19 in pregnancy described management by caesarean, strict isolation of the neonate and formula feeding. Is this practice justified? Objective To estimate the risk of the neonate becoming infected with SARS-CoV-2 by mode of delivery, type of infant feeding and mother-infant interaction. Search strategy Two biomedical databases were searched between September 2019 and June 2020. Selection criteria Case reports or case series of pregnant women with confirmed COVID-19, where neonatal outcomes were reported. Data collection and analysis Data were extracted on mode of delivery, infant infection status, infant feeding and mother-infant interaction. For reported infant infection, a critical analysis was performed to evaluate the likelihood of vertical transmission. Main results Forty nine studies included information on mode of delivery and infant infection status for 655 women and 666 neonates. In all, 28/666 (4%) tested positive postnatally. Of babies born vaginally, 8/292 (2.7%) tested positivecompared with 20/374 (5.3%) born by Caesarean. Information on feeding and baby separation were often missing, but of reported breastfed babies 7/148 (4.7%) tested positive compared with 3/56 (5.3%) for reported formula fed ones. Of babies reported as nursed with their mother 4/107 (3.7%) tested positive, compared with 6/46 (13%) for those who were reported as isolated. Conclusions Neonatal COVID-19 infection is uncommon, rarely symptomatic, and the rate of infection is no greater when the baby is born vaginally, breastfed or remains with the mother. Tweetable abstract Risk of neonatal infection with COVID-19 by delivery route, infant feeding and mother-baby interaction.

Background\ud Choosing trial outcome measures is important. When outcomes are not clinically relevant or important to parents/patients, trial evidence is less likely to be implemented into practice. This study aimed to determine optimal outcome measures for a trial of no routine gastric residual volume measurement in critically ill children.\ud Methods: A mixed methods approach: a focused literature review, parent and clinician interviews, a modified two-round Delphi and a stakeholder consensus meeting.\ud Results: The review generated 13 outcomes. 14 Pediatric Intensive Care Unit (PICU) parents proposed 3 additional outcomes, these 16 were then rated by 28 clinicians in Delphi round 1. Six further outcomes were proposed, and 22 outcomes were rated in the second round. No items were voted ‘consensus out’. The 18 ‘no-consensus’ items were voted in a face-to-face meeting by 30 participants. The final 12 outcome measures were: Time to reach energy targets; ventilator associated pneumonia; vomiting; time enteral feeds withheld per 24 hour; necrotizing enterocolitis; length of invasive ventilation; PICU length of stay; mortality; change in weight and markers of feed intolerance: parenteral nutrition administered; feed formula altered and changing to post-pyloric feeds all secondary to feed intolerance.\ud Conclusion: We have identified 12 outcomes for a trial of no gastric residual volume measurement through a multi-stage process, seeking views of parents and clinicians.\ud Clinical Relevancy statement: Twelve relevant outcomes have been identified for a trial of no routine gastric residual volume measurement in critically ill children.

Background In the UK, approximately 8% of live births are preterm (before 37 weeks gestation), more than 90% of whom are born between 30 and 36 weeks, forming the largest proportion of a neonatal units’ workload. Neonatologists are cautious in initiating full milk feeds for preterm infants due to fears of necrotising enterocolitis (NEC). There is now evidence to dispute this fear. Small studies have shown that feeding preterm infants full milk feeds enterally from birth could result in a shorter length of hospital stay, which is important to parents, clinicians and NHS services without increasing the risk of NEC. This trial aims to investigate whether full milk feeds initiated in the first 24 h after birth reduces the length of hospital stay in comparison to introduction of gradual milk feeding with IV fluids or parenteral nutrition. Methods FEED1 is a multi-centre, open, parallel group, randomised, controlled superiority trial of full milk feeds initiated on the day of birth versus gradual milk feeds for infants born at 30+0 to 32+6 (inclusive) weeks gestation. Recruitment will take place in around 40 UK neonatal units. Mothers will be randomised 1:1 to full milk feeds, starting at 60 ml/kg day, or gradual feeds, as per usual local practice. Mother’s expressed breast milk will always be the first choice of milk, though will likely be supplemented with formula or donor breast milk in the first few days. Feeding data will be collected until full milk feeds are achieved (≥ 140 ml/kg/day for 3 consecutive days). The primary outcome is length of infant hospital stay. Additional data will be collected 6 weeks post-discharge. Follow-up at 2 years (corrected gestational age) is planned. The sample size is 2088 infants to detect a between group difference in length of stay of 2 days. Accounting for multiple births, this requires 1700 women to be recruited. Primary analysis will compare the length of hospital stay between groups, adjusting for minimisation variables and accounting for multiple births. Discussion This trial will provide high-quality evidence on feeding practices for preterm infants. Full milk feeds from day of birth could result in infants being discharged sooner. Trial registration ISRCTN ISRCTN89654042. Prospectively registered on 23 September 2019: ISRCTN is a primary registry of the WHO ICTRP network, and all items from the WHO Trial Registration dataset are included.

To explore parental perspectives on the use of technology in neonatal intensive care units (NICU), and its impact during COVID-19 parental presence restrictions.Co-designed online survey targeting parents of infants admitted to a Canadian NICU from March 1st, 2020 until March 5th, 2021.Parents (n = 117) completed the survey from 38 NICUs. Large variation in policies regarding parental permission to use technology across sites was reported. Restrictive use of technology was reported as a source of parental stress. While families felt that technology helped them feel close to their infant when they could not be in the NICU, it did not replace being in-person.Large variation in policies were reported. Despite concerns about devices in NICUs, evidence on how to mitigate these concerns exists. Benefits of using technology to enhance parental experiences appear substantial. Future study is needed to inform recommendations on technology use in the NICU.

Objectives: To conduct a needs assessment with families and their healthcare team to understand the impact of restrictive family presence policies in the neonatal intensive care unit (NICU) in response to COVID-19. Background: In response to the COVID-19 pandemic, significant restrictive family presence policies were instituted in most NICUs globally intended to protect infants, families, and HCPs. However, knowledge on the impact of the stress of the pandemic and policies restricting family presence in the NICU on vulnerable neonates and their families remains limited. Methods: Individuals were eligible to participate if they were a caregiver of an infant requiring NICU care or a healthcare provider (HCP) in the NICU after March 1, 2020. Semi-structured interviews were conducted using a virtual communication platform, and transcripts were analyzed using inductive thematic qualitative content analysis. Results: Twenty-three participants were interviewed (12 families and 11 HCPs). Three themes emerged: (1) successes (family-integrated care, use of technology), (2) challenges (lack of standardized messaging and family engagement, impact on parental wellbeing, institutional barriers, and virtual care), and (3) moving forward (responsive and supportive leadership). Conclusions: Our findings highlight the significant impact of family restrictions on the mental well-being of families, physical closeness with parents, and empathetic stress to HCPs. Further study of potential long-term impact is warranted.

To determine postdischarge iron status and associated factors in very preterm infants.A retrospective cohort study was conducted through a provincial database on all very preterm infants born in Nova Scotia between 2005 and 2018. As a standard of care, all infants received prophylactic iron supplements starting at 2-4 weeks of chronological age and were tested for iron deficiency at 4 or 6 months corrected age. Iron deficiency was defined as serum ferritin20 g/L at 4 months or12 g/L at 6 months. Multivariate logistic regression analysis identified factors associated with iron deficiency.Among 411 infants, 132 (32.1%) had iron deficiency and 11 (2.7%) had iron deficiency anemia. The prevalence of iron deficiency decreased over time, from 37.6% in 2005-2011 to 25.8% in 2012-2018. Gestational hypertension in the mother (P = .01) and gestational age27 weeks (P = .02) were independent risk factors for iron deficiency. In addition, the odds of iron deficiency were lower in the mixed-fed group (ie, with breast milk and formula combined) compared with the exclusive formula-fed group (P = .01).Iron deficiency was prevalent in 32% of the very preterm infants despite early iron prophylaxis. These results demonstrate the importance of monitoring iron stores during preterm follow-up. Information about risk factors is important to mitigate iron deficiency in very preterm infants.

Objective: to determine the incidence of, and complication rates from, impacted fetal head at full dilatation Caesarean birth in the UK, and record what techniques were used.Design: prospective observational study using the UK Obstetric Surveillance System (UKOSS).Setting: 159 (82%) of the 194 UK hospitals with obstetric units.Population: all women who underwent second stage Caesarean birth in the UK between 1st March and 31st August 2019. Further information was collected on cases where a dis-impaction technique was used, or the operating surgeon experienced 'difficulty' in delivering the head.Methods: prospective observational study.Main outcome measures: technique(s) used, maternal and neonatal outcomes.Results: 3,518 s stage Caesarean births reported. The surgeon used a dis-impaction technique or reported 'difficulty' in 564 (16%) of these. The most common dis-impaction techniques used were manual elevation of the head by an assistant through the vagina (n = 235) and a fetal "pillow" (n = 176). Thirteen babies (2%) died or sustained severe injury. Four babies died (two directly attributable to the impacted fetal head).Conclusions: difficulty with delivery of the fetal head and the use of dis-impaction techniques during second stage Caesarean sections are common but there is no consensus as to the best method to achieve delivery and in what order.

Objectives of this study were to determine whether single-family room (SFR) design enhances parental presence, involvement, and maternal well-being during neonatal intensive care hospitalization. An observational cohort including mothers of infants was randomly assigned to receive care in a tertiary-level open-bay (OB) (n = 35) or SFR (n = 36). Mothers were asked to complete daily diaries documenting parental presence, involvement in care, and questionnaires examining maternal well-being. Mother and father mean presence (standard deviation) was significantly higher in the SFR-17.4 (5.2) and 13.6 (6.8)-compared to OB-11.9 (6.3) and 4.6 (3.7) hours/day. Total time spent in care activities did not differ for mothers, except SFR mothers spent more time expressing breast milk (EBM). SFR fathers had greater involvement with care activities. There were no other significant differences. The SFR was associated with greater maternal presence, but not greater involvement in care activities except for EBM, nor improved maternal well-being. The SFR appears to have greater impact on fathers' involvement in care and comforting activities, although the amount of time involved remained quite low compared with mothers. Further studies examining ways to enhance parental involvement in the neonatal intensive care unit are warranted.

Objective: To evaluate the association of a combined exposure to antenatal steroids and prophylactic indomethacin with the outcome of spontaneous intestinal perforation (SIP) among neonates born at 7 days before birth) exposures. The co-exposure was prophylactic indomethacin. The primary outcome was SIP. Multivariable logistic regression analysis was used to calculate aORs. Results: Among 4720 eligible infants, 4121 (87%) received antenatal steroids and 1045 (22.1%) received prophylactic indomethacin. Among infants exposed to antenatal steroids, those who received prophylactic indomethacin had higher odds of SIP (aOR 1.61, 95% CI 1.14-2.28) compared with no prophylactic indomethacin. Subgroup analyses revealed recent antenatal steroids exposure with prophylactic indomethacin had higher odds of SIP (aOR 1.67, 95% CI 1.15-2.43), but latent antenatal steroids exposure with prophylactic indomethacin did not (aOR 1.24, 95% CI 0.48-3.21), compared with the respective groups with no prophylactic indomethacin. Among those not exposed to antenatal steroids, mortality was lower among those who received prophylactic indomethacin (aOR 0.45, 95% CI 0.28-0.73) compared with no prophylactic indomethacin. Conclusions: In preterm neonates of

ObjectiveTo report outcomes at 2 years corrected age for children of women recruited to a trial comparing alternative policies for timing of cord clamping and immediate neonatal care at very preterm birth.DesignParallel group randomised (1:1) trial.SettingEight UK tertiary maternity units.ParticipantsTwo hundred and seventy-six babies born to 261 women expected to have a live birth before 32+0 weeks’ gestation.InterventionsDeferred cord clamping (≥2 min) and immediate neonatal care with cord intact or immediate (≤20 s) clamping and immediate neonatal care after clamping.Main outcome measureComposite of death or adverse neurodevelopmental outcome at 2 years corrected age.ResultsSix babies born after 35+6 weeks were excluded. At 2 years corrected age, outcome data were not available for a further 52 children, leaving 218 for analysis (115 deferred clamping, 103 immediate clamping). Overall, 24/115 (21%) children allocated deferred clamping died or had an adverse neurodevelopmental outcome compared with 35/103 (34%) allocated immediate clamping; risk ratio (RR) 0.61 (95% CI 0.39 to 0.96); risk difference (RD) −13% (95% CI −25% to −1%). Multiple imputation for missing data gave an RR 0.69 (95% CI 0.44 to 1.09) and RD −9% (95% CI −21% to 2%).ConclusionsDeferred clamping and immediate neonatal care with cord intact may reduce the risk of death or adverse neurodevelopmental outcome at 2 years of age for children born very premature. Confirmation in larger studies is needed to determine the real benefits and harms.Trial registration numberISRCTN21456601.

Objectives: Despite little evidence, the practice of routine measurement\ud of gastric residual volume to guide both the initiation and\ud delivery of enteral feeding in PICUs is widespread internationally.\ud In light of increased scrutiny of the evidence surrounding this\ud practice, and as part of a trial feasibility study, we aimed to determine\ud enteral feeding and gastric residual volume measurement\ud practices in U.K. PICUs.\ud Design: An online survey to 27 U.K. PICUs.\ud Setting: U.K. PICUs.\ud Subjects: A clinical nurse, senior doctor, and dietician were invited\ud to collaboratively complete one survey per PICU and send a copy of\ud their unit guidelines on enteral feeding and gastric residual volume.\ud Interventions: None.\ud Measurement and Main Results: Twenty-four of 27 units (89%)\ud approached completed the survey. Twenty-three units (95.8%;23/24) had written feeding guidelines, and 19 units (19/23;\ud 83%) sent their guidelines for review. More units fed continuously\ud (15/24; 62%) than intermittently (9/24; 37%) via the gastric route\ud as their primary feeding method. All but one PICU routinely measured\ud gastric residual volume, regardless of the method of feeding.\ud Eighteen units had an agreed definition of feed tolerance, and all\ud these included gastric residual volume. Gastric residual volume\ud thresholds for feed tolerance were either volume based (mL/kg\ud body weight) (11/21; 52%) or a percentage of the volume of\ud feed administered (6/21; 29%). Yet only a third of units provided\ud guidance about the technique of gastric residual volume measurement.\ud Conclusions: Routine gastric residual volume measurement is part\ud of standard practice in U.K. PICUs, with little guidance provided\ud about the technique which may impact the accuracy of gastric\ud residual volume. All PICUs that defined feed tolerance included\ud gastric residual volume in the definition. This is important to know\ud when proposing a standard practice arm of any future trial of no routine gastric residual volume measurement in critically ill children.

Aim A new specialised service for preterm infants with bronchopulmonary dysplasia requiring long-term oxygen therapy (LTOT) was established in 2007, led by the paediatric respiratory team, transitioning from neonatal-led follow-up. The new service included the utilisation of a clear protocol. Our objective was to review whether this service initiation led to a reduction of time in LTOT and hospital readmissions. Methods We performed a retrospective cohort study of infants born at, The implementation of a clear protocol for assessment and management of neonates with bronchopulmonary dysplasia may lead to more infants being discharged in home oxygen, but has potential to reduce overall healthcare costs and improve long-term outcomes http://ow.ly/fYcv30nIc2c

Infants born preterm are exposed to repeated painful procedures during neonatal intensive care unit admission. Particularly in preterm infants, trajectories of pain response are not well understood. The aim of this study was to classify pain response trajectories over 2 minute following medically indicated heel lances in preterm infants.This study used existing clinical trial data (NCT01561547) that evaluated the efficacy of kangaroo care and sucrose for infant pain control. Pain was measured using the Premature Infant Pain Profile at 30, 60, 90, and 120 seconds following a heel lance. Group-based trajectory modeling was used to classify pain response in this 2 minute period.A total of 236 infants with median gestational age of 33 weeks contributed 610 procedures. A model with 5 trajectory classes best fit the data. Three trajectories were stable over time at different levels of intensity from low-mild to low-moderate pain. One trajectory reflected a linear reduction from high-moderate to low-moderate pain. The final trajectory showed variable moderate-high pain. At all times points, 3 classes were at least 1-point different from the overall sample mean pain score. Only 21 (9%) infants maintained the same class for all 3 procedures.In this sample of preterm infants receiving pain relief, most pain trajectories reflected mild to low-moderate pain that was stable over 2 minute after heel lance initiation. Trajectories were not consistent over multiple procedures within infants, and an overall mean pain score for the sample may misrepresent subgroups of pain response.

Background Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness. Methods and findings Pregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model’s intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than “treat all” or “treat none” strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset. Conclusions In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice. Trial registration The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277)., Sarah J Stock and colleagues develop and validate a risk prediction model of spontaneous preterm birth for women with preterm labour symptoms, based on vaginal fluid fetal fibronectin and clinical risk factors., Author summary Why was this study done? Preterm labour is notoriously challenging for clinicians to diagnose due to the nonspecific nature of presenting signs and symptoms. The outcomes and health of preterm babies can be significantly improved by well-timed and appropriate interventions, but unnecessary overtreatment of women is common and costly. Qualitative fetal fibronectin (fFN) is one test used to aid the diagnosis of preterm labour. What did the researchers do and find? We developed and validated a risk prediction model to improve the prediction of impending preterm birth using a combination of qualitative fFN results and additional clinical risk factors. The primary outcome was spontaneous preterm birth within 7 days of fFN testing. We developed and internally validated the model using data from 1783 European women and externally validated the model in a prospective cohort study of 2,924 UK women. Women with signs and symptoms of preterm labour were included in the analysis between 22+0 to 34+6 weeks gestation. At a threshold of ≥2% risk of birth within 7 days of testing, we found the prognostic model to be cost effective in comparison to fFN alone. What do these findings mean? Our findings indicate that the prognostic model has promising potential to improve prediction of spontaneous preterm birth. The model is well placed to aid management decisions and discussions with women presenting with signs and symptoms of preterm labour. Limitations were that there were low numbers of participants in the studies who were not White, and there were some missing data in the risk predictor development cohort.

Neonatal care largely follows clinical practice guidelines and position statements developed locally by respective institutions as well as by national and international organizations. One might expect that adoption of clinical guidelines based on best available research evidence would make neonatal care practices mostly uniform. However, wide variation in clinical practice is still noted in neonatal care. Neonatal clinical guidelines are developed almost exclusively by healthcare professionals, with little or no input from families of the infants being cared for. Therefore, such variation in practice may stem not only from how the evidence is interpreted but also how caregivers and families value different outcomes that are affected by particular interventions. Acknowledging and incorporating the variability in patient and family values and preferences in clinical guidelines is an important step towards allowing shared decision making while reducing unwarranted practice variation, and thereby helping clinicians practice family-centered evidence-based medicine.

BackgroundTherapeutic hypothermia is standard of care for babies with moderate/severe hypoxic-ischaemic encephalopathy and is increasingly used for mild encephalopathy.ObjectiveDescribe temporal trends in the clinical condition of babies diagnosed with hypoxic-ischaemic encephalopathy who received therapeutic hypothermia.DesignRetrospective cohort study using data held in the National Neonatal Research Database.SettingNational Health Service neonatal units in England, Wales and Scotland.PatientsInfants born from 1 January 2010 to 31 December 2017 with a recorded diagnosis of hypoxic-ischaemic encephalopathy who received therapeutic hypothermia for at least 3 days or died in this period.Main outcomesPrimary outcomes: recorded clinical characteristics including umbilical cord pH; Apgar score; newborn resuscitation; seizures and treatment on day 1. Secondary outcomes: recorded hypoxic-ischaemic encephalopathy grade.Results5201 babies with a diagnosis of hypoxic-ischaemic encephalopathy received therapeutic hypothermia or died; annual numbers increased over the study period. A decreasing proportion had clinical characteristics of severe hypoxia ischaemia or a diagnosis of moderate or severe hypoxic-ischaemic encephalopathy, trends were statistically significant and consistent across multiple clinical characteristics used as markers of severity.ConclusionsTreatment with therapeutic hypothermia for hypoxic-ischaemic encephalopathy has increased in England, Scotland and Wales. An increasing proportion of treated infants have a diagnosis of mild hypoxic-ischaemic encephalopathy or have less severe clinical markers of hypoxia. This highlights the importance of determining the role of hypothermia in mild hypoxic-ischaemic encephalopathy. Receipt of therapeutic hypothermia is unlikely to be a useful marker for assessing changes in the incidence of brain injury over time.

Authors’ reply re: ’Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: A systematic review and critical analysis (Response to BJOG-20-1416)Kate F Walker1, Keelin O’Donoghue2, Nicky Grace3, Jon Dorling4, Jeannette L Comeau4, Wentao Li5 Jim G Thornton11Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham2The Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork, Ireland3 School of English, University of Nottingham4Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada5Department of Obstetrics and Gynaecology, Monash University, Clayton, AustraliaThank you for the opportunity to comment on the letter by Dr Xue from Shanghai Jiao Tong University. We agree there are many weaknesses in the data we reviewed. Dr Xue has identified one. Others are the incomplete reporting of infant feeding and mother-child interactions, and the frequent lack of infant testing to confirm or refute the possibility of vertical transmission of COVID-19. Finally, although we simply provided summary totals, it would be statistically preferable to combine series using the Mantel-Haenszel method and calculate a relative risk. We judged that doing this in light of the uncertainties around the data which Dr Xue has identified, might give a spurious precision to our results. As he says, more work is needed. For now we think it remains reasonable to not regard COVID-19 in itself, as an indication for Caesarean, artificial feeding or separation, in the mother and baby’s interest.

ObjectiveTo explore parents’ perceptions and experience of being approached for enrolment of their preterm infant in more than one trial or study.DesignA qualitative study involving 17 in-depth semistructured interviews, with parents who had been approached for multiple studies and who subsequently consented for their infant(s) to join at least one. Parents who declined all studies were not approached.Setting and participantsParents of preterm infants receiving care at one of three neonatal intensive care units in the north of England.FindingsMost parents did not view concurrent participation in multiple trials or studies as a significant issue within the wider context of their infant’s care. Most parents did not feel pressured into enrolling their infant into more than one study, but some suggested that participation in several provided justification for the subsequent refusal to join others, articulating feeling of guilt at saying ‘no’, and others appeared fatigued by multiple approaches. Parents focused on the perceived risks and benefits of each individual study and, while acknowledging that making a fully informed decision was not possible, largely agreed due to their belief in the benefits of research, trust in the health professionals caring for their baby and a range of complex personal motivations.ConclusionsParents valued the autonomy to make decisions about participation and felt, with hindsight, that their decisions were right. Research teams could be more aware of parental feelings of guilt or gratitude that may motivate them to give consent. Similarly, the capacity of parents to fully remember details of multiple studies when they are stressed, and their infant is sick, should be taken into consideration, and continued efforts should be made to ensure ongoing consent to participation.

ObjectivesFor very preterm births, to compare alternative policies for umbilical cord clamping and immediate neonatal care.DesignParallel group randomised (1:1) trial, using sealed opaque numbered envelopes.SettingEight UK tertiary maternity units.Participants261 women expected to have a live birth before 32 weeks, and their 276 babies.InterventionsCord clamping after at least 2 min and immediate neonatal care with cord intact, or clamping within 20 s and immediate neonatal care after clamping.Main outcome measuresIntraventricular haemorrhage (IVH), death before discharge.Results132 women (137 babies) were allocated clamping ≥2 min and neonatal care cord intact, and 129 (139) clamping ≤20 s and neonatal care after clamping; six mother-infant dyads were excluded (2, 4) as birth was after 35+6 weeks, one withdrew (death data only available) (0, 1). Median gestation was 28.9 weeks for those allocated clamping ≥2 min, and 29.2 for those allocated clamping ≤20 s. Median time to clamping was 120 and 11 s, respectively. 7 of 135 infants (5.2%) allocated clamping ≥2 min died and 15 of 135 (11.1%) allocated clamping ≤20 s; risk difference (RD) −5.9% (95% CI −12.4% to 0.6%). Of live births, 43 of 134 (32%) had IVH vs 47 of 132 (36%), respectively; RD −3.5% (−14.9% to 7.8%). There were no clear differences in other outcomes for infants or mothers.ConclusionsThis is promising evidence that clamping after at least 2 min and immediate neonatal care with cord intact at very preterm birth may improve outcome; a large trial is urgently needed.Trial registrationISRCTN 21456601.

BACKGROUND: Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. METHODS: We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery ( FINDINGS: Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. INTERPRETATION: Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. FUNDING:National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P=0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425. opens in new tab.)

Objectives: Evaluate the risk of severe intraventricular hemorrhage, in the first week of life, in preterm infants undergoing early interhospital transport.Design: Retrospective cohort study.Setting: Tertiary neonatal centers of the Trent Perinatal Network in the United Kingdom.Patients: Preterm infants less than 32 weeks gestation, who were either born within and remained at the tertiary neonatal center (inborn), or were transferred (transported) between centers in the first 72 hours of life.Interventions: None.Measurements and Main Results: Multivariable logistic regression models adjusting for key confounders were used to calculate odds ratios for intraventricular hemorrhage with 95% CIs for comparison of inborn and transported infants. Cranial ultrasound findings on day 7 of life. Secondary analyses were performed for antenatal steroid course and gestational age subgroups. A total of 1,047 preterm infants were included in the main analysis. Transported infants (n = 391) had a significantly higher risk of severe (grade III/IV) intraventricular hemorrhage compared with inborns (n = 656) (9.7% vs 5.8%; adjusted odds ratio, 1.69; 95% CI, 1.04–2.76), especially for infants born at less than 28 weeks gestation (adjusted odds ratio, 1.83; 95% CI, 1.03–3.21). Transported infants were less likely to receive a full antenatal steroid course (47.8% vs 64.3%; p < 0.001). A full antenatal steroid course significantly decreased the risk of severe intraventricular hemorrhage irrespective of transport status (odds ratio, 0.33; 95% CI, 0.2–0.55). However, transported infants less than 28 weeks gestation remained significantly more likely to develop a severe intraventricular hemorrhage despite a full antenatal steroid course (adjusted odds ratio, 2.84; 95% CI, 1.08–7.47).Conclusions: Preterm infants transported in the first 72 hours of life have an increased risk of early-life severe intraventricular hemorrhage even when maternal antenatal steroids are given. The additional burden of postnatal transport could be an important component in the pathway to severe intraventricular hemorrhage. As timely in-utero transfer is not always possible, we need to focus research on improving the transport pathway to reduce this additional risk.

Background: Iron is an essential micronutrient, especially in infants and young children and is required for erythropoiesis and development of the central nervous system. However, iron deficiency (ID) is the most common micronutrient deficiency worldwide. ID and iron deficiency anemia (IDA) have been associated with poor neurodevelopmental and behavioural outcomes later in life. Preterm infants are particularly at risk of developing ID in early life due to lower iron stores at birth, accelerated growth in the first weeks of life and multiple phlebotomies while in hospital. Therefore, international recommendations suggest prophylactic iron therapy of 2-4 mg/kg/day starting at 2-6 weeks of age until at least 6-12 months in preterm and low birth weight infants. This prophylactic iron supplementation has been shown to be effective at reducing the incidence of ID and IDA. However, the published work mainly involves moderate to late preterm infants and the research is lacking on iron status after discharge in very preterm infants (VPI, Objective: To investigate the risk factors associated with development of ID Methods: A retrospective cohort study was conducted at the IWK Health Centre using a population based provincial Perinatal Follow-Up Program database. All live-born VPIs born in Nova Scotia between 2005-2018 were included. Patients with congenital malformations, chromosomal anomalies, or who died prior to outcome assessment were excluded. As a standard of care, all these infants were started on prophylactic iron supplements (2-3 mg/kg/day) at 2-4 weeks of chronological age. Iron dosage was regularly adjusted during the hospital stay as guided by serum ferritin levels. At discharge, it was recommended to continue iron prophylaxis until 9-12 months corrected age. All these infants underwent a blood test during their first neonatal follow-up visit at 4-6 months corrected age to check for hemoglobin, reticulocyte count and serum ferritin. ID was defined as serum ferritin Results: Of 411 infants included in the study, 32.1% (n=132) had ID. The prevalence of ID decreased over time (37.6% in 2005-2011 vs 25.8% in 2012-2018 cohort). Table 1 compares the antenatal and neonatal characteristics of the ID and non-ID groups. Table 2 compares sociodemographic variables and clinical variables at the time of follow up of the two groups. Independent risk factors for ID were: gestational age (27 weeks) (OR:1.7 (1.0-2.9), p=0.04) and gestational hypertension (OR: 2.1(1.2-3.7), p=0.009). Independent factors protective for ID were: mixed feeding (breast milk and formula compared to formula alone) (OR: 0.5 (0.2-0.9), p=0.021) and iron supplementation at follow-up (OR:0.5 (0.3-0.9), p=0.02). Conclusion(s): Despite prophylactic iron supplementation, one-third of VPIs had ID at 4-6 months corrected age. Gestational hypertension in mother and gestational age < 27 weeks were independent risk factors for ID. In addition, despite adjusting for iron supplementation at follow-up, the formula feeding group was more likely to have ID compared to the mixed feeding group. This may be because of the sub-therapeutic iron intake in the formula fed infants. It is often thought that formula milk may have sufficient iron to meet the demands of growing infants and thus, they are less likely to receive higher doses of supplemental iron beyond what is contained in the formula. However, this may not be true since the iron present in formula may not have the same bioavailability as breast milk. Future prospective studies are required to further validate these observations. Nonetheless, the study identified important areas to mitigate ID in VPIs. Disclosures No relevant conflicts of interest to declare.

To evaluate the rates of practice, and the associations between different cord management strategies at birth (delayed cord clamping [DCC], umbilical cord milking [UCM], and early cord clamping [ECC]) and mortality or major morbidity, rates of blood transfusion, and peak serum bilirubin in a large national cohort of very preterm infants.We retrospectively studied preterm infants33 weeks of gestation admitted to the Canadian Neonatal Network between January 2015 and December 2017. Patients who received ECC (30 seconds), UCM, or DCC (≥30 seconds) were compared. Multiple generalized linear/quantile logistic regression models were used.Of 12 749 admitted infants, 9729 were included; 4916 (50.5%) received ECC, 394 (4.1%) UCM, and 4419 (45.4%) DCC. After adjustment for potential confounders identified between groups in univariate analyses, the odds of mortality or major morbidity were higher in the ECC group when compared with UCM group (aOR, 1.18; 95% CI, 1.03-1.35). Mortality and intraventricular hemorrhage were associated with ECC as compared with DCC (aOR, 1.6 [95% CI, 1.22-2.1] and aOR, 1.29 [95% CI, 1.19-1.41], respectively). The odds of severe intraventricular hemorrhage were higher with UCM compared with DCC (aOR, 1.38; 95% CI, 1.05-1.81). Rates of blood transfusion were higher with ECC compared with UCM and DCC (aOR, 1.67 [95% CI, 1.31-2.14] and aOR, 1.68 [95% CI, 1.35-2.09], respectively), although peak serum bilirubin levels were not significantly different.Both DCC and UCM were associated with better short-term outcomes than ECC; however, the odds of severe intraventricular hemorrhage were higher with UCM compared with DCC.

Background Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question. Methods The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks’ gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks’ gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks’ gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care. Discussion Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines. Trial registration ISRCTN registry, ID: ISRCTN91918806. Prospectively registered on 27 August 2015. Electronic supplementary material The online version of this article (10.1186/s13063-018-3018-4) contains supplementary material, which is available to authorized users.

In a multi-centre randomised controlled trial (RCT), we are assessing whether giving very preterm (i.e., born at < 32 weeks’ gestation) infants prophylactic enteral bovine lactoferrin supplementation (150 mg/kg/day) from shortly after birth until 34 weeks’ post-menstrual age reduces the incidence of late-onset invasive infection (primary outcome), all-cause mortality, bronchopulmonary dysplasia, necrotising enterocolitis, retinopathy of prematurity, and the duration of antibiotic exposure, intensive care, and hospital admission. The trial is recruiting 2,200 participants from 37 neonatal care centres in the UK over 4 years. We will undertake an economic evaluation within the RCT to evaluate cost-effectiveness and provide an estimate of incremental costs for differences in the pre-specified outcomes in primary and subgroup analyses. If a statistically significant and clinically important effect on the primary outcome is detected, we will seek further funding and approval to assess the impact of enteral lactoferrin supplementation on rates of adverse neuro-developmental outcomes in the participating infants when they are 5 years old.

Background: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein usually processed from cow's milk, prevents infections and associated complications. Methods: In this randomised, placebo-controlled trial, very preterm infants (born before 32 weeks' gestation) were recruited within 72 hours of birth from 37 UK hospitals. Infants were allocated randomly (1:1) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose (same dose) once daily until 34 weeks' postmenstrual age. Web-based randomisation used an algorithm minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers and outcomes assessors were unaware of group assignment. The primary outcome was microbiologically-confirmed or clinically-suspected late-onset infection until hospital discharge. The trial was registered with the International Standard Randomised Controlled Trial Number 88261002. Findings: We recruited 2203 participants between May 2014 and September 2017. Four infants had consent withdrawn or unconfirmed leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants were available for inclusion in the intention-to-treat analyses. In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: risk ratio (RR) adjusted for minimisation factors 0.95 (95% confidence interval [CI] 0.81, 1.10). Pre-specified subgroup analyses did not show statistically significant interactions for gestation at birth (completed weeks') or type of enteral milk received (human, formula, or both). Interpretation: Enteral supplementation with bovine lactoferrin does not reduce the incidence of late-onset infection in very preterm infants. Trial Registration Number: The trial was registered with the International Standard Randomised Controlled Trial Number 88261002. Funding: The ELFIN trial was funded by the UK National Institute for Health Research Health Technology Assessment programme (10/57/49). Declaration of Interest: EJ is a member of the NIHR HTA General Board; WM is a member of the NIHR HTA Commissioning Board and the HTA Journals Library Editorial Board. JD is a member of the NIHR HTA Clinical Evaluation and Trials Board. PTH, WM, EJ, LL report receipt of funding from NIHR, outside the submitted work. NDE reports grants from Prolacta Biosciences US, grants from Danone Early Life Nutrition, personal fees from Nestle Nutrition Institute, and personal fees from Baxter, outside the submitted work. Ethical Approval: The trial protocol was approved by the National Research Ethics Service (NRES) Committee East Midlands - Nottingham 2 (Ref: 13/EM/0118). Local approval and site-specific assessments were obtained from the NHS Trusts for trial sites.

Background Gastro-oesophageal reflux (GOR) is common in infants, and feed thickeners are often used to manage it in infants as they are simple to use and perceived to be harmless. However, conflicting evidence exists to support the use of feed thickeners. Objectives To evaluate the use of feed thickeners in infants up to six months of age with GOR in terms of reduction in a) signs and symptoms of GOR, b) reflux episodes on pH probe monitoring or intraluminal impedance or a combination of both, or c) histological evidence of oesophagitis. Search methods We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2), MEDLINE via PubMed (1966 to 22 November 2016), Embase (1980 to 22 November 2016), and CINAHL (1982 to 22 November 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials. Selection criteria We included randomised controlled trials if they examined the effects of feed thickeners as compared to unthickened feeds (no treatment or placebo) in treating GOR in term infants up to six months of age or six months of corrected gestational age for those born preterm. Data collection and analysis Two review authors independently identified eligible studies from the literature search. Two review authors independently performed data extraction and quality assessments of the eligible studies. Differences in opinion were resolved by discussion with a third review author, and consensus was reached among all three review authors.We used the GRADE approach to assess the quality of the evidence. Main results Eight trials recruiting a total of 637 infants met the inclusion criteria for the systematic review. The infants included in the review were mainly formula-fed term infants. The trials were of variable methodological quality. Formula-fed term infants with GOR on feed thickeners had nearly two fewer episodes of regurgitation per day (mean difference -1.97 episodes per day, 95% confidence interval (CI) -2.32 to -1.61; 6 studies, 442 infants, moderate-certainty evidence) and were 2.5 times more likely to be asymptomatic from regurgitation at the end of the intervention period (risk ratio 2.50, 95% CI 1.38 to 4.51; number needed to treat for an additional beneficial outcome 5, 95% CI 4 to 13; 2 studies, 186 infants, low-certainty evidence) when compared to infants with GOR on unthickened feeds. No studies reported failure to thrive as an outcome. We found low-certainty evidence based on 2 studies recruiting 116 infants that use of feed thickeners improved the oesophageal pH probe parameters of reflux index (i.e. percentage of time pH < 4), number of reflux episodes lasting longer than 5 minutes, and duration of longest reflux episode. No major side effects were reported with the use of feed thickeners. Information was insufficient to conclude which type of feed thickener is superior. Authors’ conclusions Gastro-oesophageal reflux is a physiological self resolving phenomenon in infants that does not necessarily require any treatment. However, we found moderate-certainty evidence that feed thickeners should be considered if regurgitation symptoms persist in term bottle-fed infants. The reduction of two episodes of regurgitation per day is likely to be of clinical significance to caregivers. Due to the limited information available, we were unable to assess the use of feed thickeners in infants who are breastfeeding or preterm nor could we conclude which type of feed thickener is superior.

Large randomized controlled trials (RCTs) in preterm infants offer unique opportunities for mechanistic evaluation of the risk factors leading to serious diseases, as well as the actions of interventions designed to prevent them. Necrotizing enterocolitis (NEC) a serious inflammatory gut condition and late-onset sepsis (LOS) are common feeding and nutrition-related problems that may cause death or serious long-term morbidity and are key outcomes in two current UK National Institutes for Health Research (NIHR) trials. Speed of increasing milk feeds trial (SIFT) randomized preterm infants to different rates of increases in milk feeds with a primary outcome of survival without disability at 2 years corrected age. Enteral lactoferrin in neonates (ELFIN) randomizes infants to supplemental enteral lactoferrin or placebo with a primary outcome of LOS. This is a protocol for the mechanisms affecting the gut of preterm infants in enteral feeding trials (MAGPIE) study and is funded by the UK NIHR Efficacy and Mechanistic Evaluation programme. MAGPIE will recruit ~480 preterm infants who were enrolled in SIFT or ELFIN. Participation in MAGPIE does not change the main trial protocols and uses non-invasive sampling of stool and urine, along with any residual resected gut tissue if infants required surgery. Trial interventions may involve effects on gut microbes, metabolites (e.g., short-chain fatty acids), and aspects of host immune function. Current hypotheses suggest that NEC and/or LOS are due to a dysregulated immune system in the context of gut dysbiosis, but mechanisms have not been systematically studied within large RCTs. Microbiomic analysis will use next-generation sequencing, and metabolites will be assessed by mass spectrometry to detect volatile organic and other compounds produced by microbes or the host. We will explore differences between disease cases and controls, as well as exploring the actions of trial interventions. Impacts of this research are multiple: translation of knowledge of mechanisms promoting gut health may explain outcomes or suggest alternate strategies to improve health. Results may identify new non-invasive diagnostic or monitoring techniques, preventative or treatment strategies for NEC or LOS, or provide data useful for risk stratification in future studies. Mechanistic evaluation might be especially informative where there are not clear effects on the primary outcome (ISRCTN 12554594).

Paediatric and adult resuscitation is often performed with family present. Current guidelines recommend deferred umbilical cord clamping as part of immediate neonatal care, requiring neonatal assessment next to the mother. This paper describes strategies for providing care beside the mother using both standard resuscitation equipment and a trolley designed for this purpose.