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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 Second-stage caesarean sections, of which there are around 34,000 per year in the UK, have greater maternal and perinatal morbidity than those in the first stage. The fetal head is often deeply impacted in the maternal pelvis, and extraction can be difficult. Numerous techniques are reported, but the superiority of one over another is contentious and there is no national guidance. Objective To determine the feasibility of a randomised trial of different techniques for managing an impacted fetal head during emergency caesarean. Design A scoping study with five work packages: (1) national surveys to determine current practice and acceptability of research in this area, and a qualitative study to determine acceptability to women who have experienced a second-stage caesarean; (2) a national prospective observational study to determine incidence and rate of complications; (3) a Delphi survey and consensus meeting on choice of techniques and outcomes for a trial; (4) the design of a trial; and (5) a national survey and qualitative study to determine acceptability of the proposed trial. Setting Secondary care. Participants Health-care professionals, pregnant women, women who have had a second-stage caesarean, and parents. Results Most (244/279, 87%) health-care professionals believe that a trial in this area would help guide their practice, and 90% (252/279) would be willing to participate in such a trial. Thirty-eight per cent (98/259) of parents reported that they would take part. Women varied in which technique they thought was most acceptable. Our observational study found that impacted head is common (occurring in 16% of second-stage caesareans) and leads to both maternal (41%) and neonatal (3.5%) complications. It is most often treated by an assistant pushing the head up vaginally. We designed a randomised clinical trial comparing the fetal pillow with the vaginal push technique. The vast majority of health-care professionals, 83% of midwives and 88% of obstetricians, would be willing to participate in the trial proposed, and 37% of parents reported that they would take part. Our qualitative study found that most participants thought the trial would be feasible and acceptable. Limitations Our survey is subject to the limitation that, although responses refer to contemporaneous real cases, they are self-reported by the surgeon and collected after the event. Willingness to participate in a hypothetical trial may not translate into recruitment to a real trial. Conclusions We proposed a trial to compare a new device, the fetal pillow, with a long-established procedure, the vaginal push technique. Such a trial would be widely supported by health-care professionals. We recommend that it be powered to test an effect on important short term maternal and baby outcomes which would require 754 participants per group. Despite the well-known difference between intent and action, this would be feasible within the UK. Future work We recommend a randomised controlled trial of two techniques for managing an impacted fetal head with an in-built internal pilot phase and alongside economic and qualitative substudies. Study registration This study is registered as Research Registry 4942. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 6. See the NIHR Journals Library website for further project information.

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 Loss to follow-up resulting in missing outcomes compromises the validity of trial results by reducing statistical power, negatively affecting generalisability and undermining assumptions made at analysis, leading to potentially biased and misleading results. Evidence that incentives are effective at improving response rates exists, but there is little evidence regarding the best approach, especially in the field of perinatal medicine. The NIHR-funded SIFT trial follow-up of infants at 2 years of age provided an ideal opportunity to address this remaining uncertainty. Methods Participants: parents of infants from participating neonatal units in the UK and Ireland followed up for SIFT (multicentre RCT investigating two speeds of feeding in babies with gestational age at birth Results Parents of 923 infants were randomised: 459 infants allocated to receive incentive before, 464 infants allocated to receive incentive after; analysis was by intention to treat. Allocation to the incentive before completion led to a significantly higher response rate, 83.0% (381/459) compared to the after-completion group, 76.1% (353/464); adjusted absolute difference of 6.8% (95% confidence interval 1.6% to 12.0%). Giving an incentive in advance is the more costly approach, but the mean difference of ~£3 per infant is small given the higher return. Conclusions An unconditional incentive in advance led to a significantly higher response rate compared to the promise of an incentive on completion. Against a backdrop of falling response rates to questionnaires, incentives can be an effective way to increase returns. Trial registration SIFT (ISRCTN76463425). Registered on March 5, 2013.; SWAT registration (SWAT 69 available from http://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/FileStore/Filetoupload,864297,en.pdf). Registered on June 27, 2016.

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.

Objective To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy (ICP), based on their presenting characteristics, would benefit from treatment with ursodeoxycholic acid (UDCA). Design Secondary analysis of the PITCHES trial (ISRCTN91918806). Setting United Kingdom. Population or Sample 527 women with ICP. Methods Subgroup analyses were performed to determine whether baseline bile acid concentrations or baseline itch scores moderated a woman’s response to treatment with UDCA. Main outcome measures Bile acid concentration and itch score. Results In women with baseline bile acid concentrations less than 40 μmol/l, treatment with UDCA resulted in increased post‐randomisation bile acid concentrations (geometric mean ratio 1.19, 95% CI 1.00–1.41, P = 0.048). A test of interaction showed no significance (P = 0.647). A small, clinically insignificant difference was seen in itch response in women with a high baseline itch score (–6.0 mm, 95% CI −11.80 to −0.21, P = 0.042), with a test of interaction not showing significance (P = 0.640). Further subgroup analyses showed no significance. Across all women there was a weak relationship between bile acid concentrations and itch severity. Conclusions There was no subgroup of women with ICP in whom a beneficial effect of treatment with UDCA on bile acid concentration or itch score could be identified. This confirms that its routine use in women with this condition for improvement of bile acid concentration or itch score should be reconsidered. Tweetable abstract PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus., Tweetable abstract PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus.

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.

Perinatal trials sometimes require rapid recruitment processes to facilitate inclusion of participants when interventions are time-critical. A two-stage consent pathway has been used in some trials and is supported by national guidance. This pathway includes seeking oral assent for participation during the time-critical period followed by informed written consent later. This approach is being used in the fluids exclusively enteral from day one (FEED1) trial where participants need to be randomised within 3 hours of birth. There is some apprehension about approaching parents for participation via the oral assent pathway. The main reasons for this are consistent with previous research: lack of a written record, lack of standardised information and unfamiliarity with the process. Here, we describe how the pathway has been implemented in the FEED1 trial and the steps the trial team have taken to support sites. We provide recommendations for future trials to consider if they are considering implementing a similar pathway. Trial registration number:ISRCTN89654042.

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.