Systematic review of Apgar scores & cyanosis in Black, Asian, and ethnic minority infants.

BACKGROUND: Apgar score and cyanosis assessment may disadvantage darker-skinned babies. This review explored cyanosis and Apgar score assessments in Black, Asian, or minority ethnic neonates compared to White neonates. MATERIAL AND METHODS: Four databases were searched. Studies of any methodology were included. A narrative synthesis was undertaken. RESULTS: Ten studies were included. Three studies involving over 39 million neonates showed Apgar score ≤3 was predictive of neonatal mortality across all ethnicities. Black babies with Apgar score ≤3 had lower mortality rates before 28 days, however, variations in scoring practices were also observed. Three further studies (n = 39,290,014) associated low Apgar scores with poorer mental development up to 22 months, especially in mixed ethnicity and Black infants. One study reported inadequate training in assessing ethnic minority neonates. Cyanosis was the focus of three included studies (n = 455) revealing poor visual assessment of cyanosis across ethnicities. With pulse oximetry occult hypoxemia occurred slightly more frequently in Black neonates. Tongue color indicated oxygen requirement at birth, regardless of ethnicity. CONCLUSIONS: Apgar scores correlate well with neonatal mortality in all ethnicities, however scoring variations exist. Cyanosis assessment is challenging, with tongue and lips the best places to observe in the absence of pulse oximetry. IMPACT: Assessment of the color component of the Apgar score and of cyanosis visually are not accurate in babies with darker skin. Small racial differences may exist for pulse oximetry in neonates, but it is more reliable than visual assessment.

A review of the current policies and guidance regarding Apgar scoring and the detection of jaundice and cyanosis concerning Black, Asian and ethnic minority neonates.

BACKGROUND: Ethnic inequalities in maternal and neonatal health in the UK are well documented. Concerns exist regarding the use of skin colour in neonatal assessments. Healthcare professionals should be trained to recognise symptoms of diverse skin tones, and comprehensive, and inclusive guidance is necessary for the safe assessment of all infants. Disparities in healthcare provision have been emphasised during the COVID-19 pandemic, and additional research is needed to determine whether such policies adequately address ethnic minority neonates. METHODS: A desktop search included searches of guidance produced for the United Kingdom (UK). Further searches of the Cochrane and World Health Organization (WHO) were used to identify any international guidance applicable in the UK context. RESULTS: Several policies and one training resource used descriptors 'pink,' 'pale,' 'pallor,' and 'blue' about neonatal skin and mucous membrane colour. No policies provided specific guidance on how these colour descriptors may appear in neonates with different skin pigmentation. Only the NICE guidance and HEE e-learning resource acknowledged the challenges of assessing jaundice in infants with diverse skin tones, while another guideline noted differences in the accuracy of bilirubin measurements for the assessment of jaundice. Three policies and one training resource advised against relying on visual observation of skin colour when diagnosing neonatal conditions. The training resource included images of ethnic minority neonates, although most images included white infants. CONCLUSIONS: Inadequate consideration of ethnicity in UK policy and training perpetuates disparities, leading to inaccurate assessments. A review is needed for inclusivity in neonatal care, regardless of skin pigmentation.

Induction of labour at 39 weeks and adverse outcomes in low-risk pregnancies according to ethnicity, socioeconomic deprivation, and parity: A national cohort study in England.

BACKGROUND: Ethnic and socioeconomic inequalities in obstetric outcomes are well established. However, the role of induction of labour (IOL) to reduce these inequalities is controversial, in part due to insufficient evidence. This national cohort study aimed to identify adverse perinatal outcomes associated with IOL with birth at 39 weeks of gestation ("IOL group") compared to expectant management ("expectant management group") according to maternal characteristics in women with low-risk pregnancies. METHODS AND FINDINGS: All English National Health Service (NHS) hospital births between January 2018 and March 2021 were examined. Using the Hospital Episode Statistics (HES) dataset, maternal and neonatal data (demographic, diagnoses, procedures, labour, and birth details) were linked, with neonatal mortality data from the Office for National Statistics (ONS). Women with a low-risk pregnancy were identified by excluding pregnancies with preexisting comorbidities, previous cesarean section, breech presentation, placenta previa, gestational diabetes, or a baby with congenital abnormalities. Women with premature rupture of membranes, placental abruption, hypertensive disorders of pregnancy, amniotic fluid abnormalities, or antepartum stillbirth were excluded only from the IOL group. Adverse perinatal outcome was defined as stillbirth, neonatal death, or neonatal morbidity, the latter identified using the English composite neonatal outcome indicator (E-NAOI). Binomial regression models estimated risk differences (with 95% confidence intervals (CIs)) between the IOL group and the expectant management group, adjusting for ethnicity, socioeconomic background, maternal age, parity, year of birth, and birthweight centile. Interaction tests examined risk differences according to ethnicity, socioeconomic background, and parity. Of the 1 567 004 women with singleton pregnancies, 501 072 women with low-risk pregnancies and with sufficient data quality were included in the analysis. Approximately 3.3% of births in the IOL group (1 555/47 352) and 3.6% in the expectant management group (16 525/453 720) had an adverse perinatal outcome. After adjustment, a lower risk of adverse perinatal outcomes was found in the IOL group (risk difference -0.28%; 95% CI -0.43%, -0.12%; p = 0.001). This risk difference varied according to socioeconomic background from 0.38% (-0.08%, 0.83%) in the least deprived to -0.48% (-0.76%, -0.20%) in the most deprived national quintile (p-value for interaction = 0.01) and by parity with risk difference of -0.54% (-0.80%, -0.27%) in nulliparous women and -0.15% (-0.35%, 0.04%) in multiparous women (p-value for interaction = 0.02). There was no statistically significant evidence that risk differences varied according to ethnicity (p = 0.19). Key limitations included absence of additional confounding factors such as smoking, BMI, and the indication for induction in the HES datasets, which may mean some higher risk pregnancies were included. CONCLUSIONS: IOL with birth at 39 weeks was associated with a small reduction in the risk of adverse perinatal outcomes, with 360 inductions in low-risk pregnancies needed to avoid 1 adverse outcome. The risk reduction was mainly present in women from more socioeconomically deprived areas and in nulliparous women. There was no significant risk difference found by ethnicity. Increased uptake of IOL at 39 weeks, especially in women from more socioeconomically deprived areas, may help reduce inequalities in adverse perinatal outcomes.

The effect of maternal BMI, smoking and alcohol on congenital heart diseases: a Mendelian randomisation study.

BACKGROUND: Congenital heart diseases (CHDs) remain a significant cause of infant morbidity and mortality. Epidemiological studies have explored maternal risk factors for offspring CHDs, but few have used genetic epidemiology methods to improve causal inference. METHODS: Three birth cohorts, including 65,510 mother/offspring pairs (N = 562 CHD cases) were included. We used Mendelian randomisation (MR) analyses to explore the effects of genetically predicted maternal body mass index (BMI), smoking and alcohol on offspring CHDs. We generated genetic risk scores (GRS) using summary data from large-scale genome-wide association studies (GWAS) and validated the strength and relevance of the genetic instrument for exposure levels during pregnancy. Logistic regression was used to estimate the odds ratio (OR) of CHD per 1 standard deviation (SD) higher GRS. Results for the three cohorts were combined using random-effects meta-analyses. We performed several sensitivity analyses including multivariable MR to check the robustness of our findings. RESULTS: The GRSs associated with the exposures during pregnancy in all three cohorts. The associations of the GRS for maternal BMI with offspring CHD (pooled OR (95% confidence interval) per 1SD higher GRS: 0.95 (0.88, 1.03)), lifetime smoking (pooled OR: 1.01 (0.93, 1.09)) and alcoholic drinks per week (pooled OR: 1.06 (0.98, 1.15)) were close to the null. Sensitivity analyses yielded similar results. CONCLUSIONS: Our results do not provide robust evidence of an effect of maternal BMI, smoking or alcohol on offspring CHDs. However, results were imprecise. Our findings need to be replicated, and highlight the need for more and larger studies with maternal and offspring genotype and offspring CHD data.

Health care utilisation and education outcomes of children with rare diseases: a born in Bradford cohort study.

The purpose of this study is to describe the burden of health care utilisation and early education outcomes of children with and without rare diseases. Using the Born in Bradford birth cohort and its linked routine health care and education data, we looked at cumulative primary care episodes, hospital admissions and medication prescriptions. We assessed education outcomes using Early Years Foundation Stage Profile and the National Curriculum Tests-Key Stage 1 results. Among analytical sample of 13,858, 1711 or 12.3% children were identified with a rare disease by an average age of 14 years. Children with rare diseases were twice more likely to be admitted to hospital compared to children without. Average length of stay was around 5 days in those with rare diseases group compared to less than 1 day in those without. The average number of primary care episodes was 45.4 in children with rare diseases and 28.2 visits in those without. These children were over three times more likely to be on multiple medications. Children with rare diseases had 30% higher risk of being below academic expectations at Foundation Year and, depending on subject, between 50 and 60% higher risks at KS1 tests.  Conclusions: Children with rare diseases are significantly more likely to have increased primary care episodes and to have more regular medications. They are likely to have more hospital admissions with a longer stay also. Educationally, they are at higher risk of failing to achieve expected standards in early-year settings. What is Known: • Existing studies of rare diseases have used cross sectional data to describe secondary care data. Previous research has not explored the impact of rare diseases on academic outcomes in children. What is New: • Using Born in Bradford birth cohort and its linked primary and secondary care data, this study provides the most comprehensive estimate of prevalence of rare diseases in any study to date. Children with rare diseases were not only significantly more likely to have contact with primary care and to be admitted to hospitals; they were also more like to be on more regular medications and had higher risk of not achieving expected standards in early-year education outcomes. • Our study is unusual in being able to access linked health and education data and reinforces the importance of adopting a whole system approach to children's health and wellbeing that recognises the close links between health and education.

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity in very preterm or VLBW infants. OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and associated mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the Maternity and Infant Care database, and CINAHL from inception to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing probiotics with placebo or no probiotics in very preterm infants (born before 32 weeks' gestation) and VLBW infants (weighing less than 1500 g at birth). DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with associated 95% confidence intervals (CIs). The primary outcomes were NEC and all-cause mortality; secondary outcome measures were late-onset invasive infection (more than 48 hours after birth), duration of hospitalisation from birth, and neurodevelopmental impairment. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 60 trials with 11,156 infants. Most trials were small (median sample size 145 infants). The main potential sources of bias were unclear reporting of methods for concealing allocation and masking caregivers or investigators in about half of the trials. The formulation of the probiotics varied across trials. The most common preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., andStreptococcus spp., alone or in combination. Very preterm or very low birth weight infants Probiotics may reduce the risk of NEC (RR 0.54, 95% CI 0.46 to 0.65; I² = 17%; 57 trials, 10,918 infants; low certainty). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI 25 to 50). Probiotics probably reduce mortality slightly (RR 0.77, 95% CI 0.66 to 0.90; I² = 0%; 54 trials, 10,484 infants; moderate certainty); the NNTB was 50 (95% CI 50 to 100). Probiotics probably have little or no effect on the risk of late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; I² = 22%; 49 trials, 9876 infants; moderate certainty). Probiotics may have little or no effect on neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26; I² = 0%; 5 trials, 1518 infants; low certainty). Extremely preterm or extremely low birth weight infants Few data were available for extremely preterm or extremely low birth weight (ELBW) infants. In this population, probiotics may have little or no effect on NEC (RR 0.92, 95% CI 0.69 to 1.22, I² = 0%; 10 trials, 1836 infants; low certainty), all-cause mortality (RR 0.92, 95% CI 0.72 to 1.18; I² = 0%; 7 trials, 1723 infants; low certainty), or late-onset invasive infection (RR 0.93, 95% CI 0.78 to 1.09; I² = 0%; 7 trials, 1533 infants; low certainty). No trials provided data for measures of neurodevelopmental impairment in extremely preterm or ELBW infants. AUTHORS' CONCLUSIONS: Given the low to moderate certainty of evidence for the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or VLBW infants, and particularly for extremely preterm or ELBW infants, there is a need for further large, high-quality trials to provide evidence of sufficient validity and applicability to inform policy and practice.

Prebiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Dietary supplementation with prebiotic oligosaccharides to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or very low birth weight (VLBW) infants. OBJECTIVES: To assess the benefits and harms of enteral supplementation with prebiotics (versus placebo or no treatment) for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care database and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing prebiotics with placebo or no prebiotics in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. The primary outcomes were NEC and all-cause mortality, and the secondary outcomes were late-onset invasive infection, duration of hospitalisation since birth, and neurodevelopmental impairment. DATA COLLECTION AND ANALYSIS: Two review authors separately evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference (MD), with associated 95% confidence intervals (CIs). The primary outcomes of interest were NEC and all-cause mortality; our secondary outcome measures were late-onset (> 48 hours after birth) invasive infection, duration of hospitalisation, and neurodevelopmental impairment. We used the GRADE approach to assess the level of certainty of the evidence. MAIN RESULTS: We included seven trials in which a total of 705 infants participated. All the trials were small (mean sample size 100). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were potential sources of bias in three of the trials. The studied prebiotics were fructo- and galacto-oligosaccharides, inulin, and lactulose, typically administered daily with enteral feeds during birth hospitalisation. Meta-analyses of data from seven trials (686 infants) suggest that prebiotics may result in little or no difference in NEC (RR 0.97, 95% CI 0.60 to 1.56; RD none fewer per 1000, 95% CI 50 fewer to 40 more; low-certainty evidence), all-cause mortality (RR 0.43, 95% CI 0.20 to 0.92; 40 per 1000 fewer, 95% CI 70 fewer to none fewer; low-certainty evidence), or late-onset invasive infection (RR 0.79, 95% CI 0.60 to 1.06; 50 per 1000 fewer, 95% CI 100 fewer to 10 more; low-certainty evidence) prior to hospital discharge. The certainty of this evidence is low because of concerns about the risk of bias in some trials and the imprecision of the effect size estimates. The data available from one trial provided only very low-certainty evidence about the effect of prebiotics on measures of neurodevelopmental impairment (Bayley Scales of Infant Development (BSID) Mental Development Index score < 85: RR 0.84, 95% CI 0.25 to 2.90; very low-certainty evidence; BSID Psychomotor Development Index score < 85: RR 0.24, 95% 0.03 to 2.00; very low-certainty evidence; cerebral palsy: RR 0.35, 95% CI 0.01 to 8.35; very low-certainty evidence). AUTHORS' CONCLUSIONS: The available trial data provide low-certainty evidence about the effects of prebiotics on the risk of NEC, all-cause mortality before discharge, and invasive infection, and very low-certainty evidence about the effect on neurodevelopmental impairment for very preterm or VLBW infants. Our confidence in the effect estimates is limited; the true effects may be substantially different. Large, high-quality trials are needed to provide evidence of sufficient validity to inform policy and practice decisions.

Bubble devices versus other pressure sources for nasal continuous positive airway pressure in preterm infants.

BACKGROUND: Several types of pressure sources, including underwater bubble devices, mechanical ventilators, and the Infant Flow Driver, are used for providing continuous positive airway pressure (CPAP) to preterm infants with respiratory distress. It is unclear whether the use of bubble CPAP versus other pressure sources is associated with lower rates of CPAP treatment failure, or mortality and other morbidity.  OBJECTIVES: To assess the benefits and harms of bubble CPAP versus other pressure sources (mechanical ventilators or Infant Flow Driver) for reducing treatment failure and associated morbidity and mortality in newborn preterm infants with or at risk of respiratory distress. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2023, Issue 1); MEDLINE (1946 to 6 January 2023), Embase (1974 to 6 January 2023), Maternity & Infant Care Database (1971 to 6 January 2023), and the Cumulative Index to Nursing and Allied Health Literature (1982 to 6 January 2023). We searched clinical trials databases and the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials comparing bubble CPAP with other pressure sources (mechanical ventilators or Infant Flow Driver) for the delivery of nasal CPAP to preterm infants. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of the evidence for effects on treatment failure, all-cause mortality, neurodevelopmental impairment, pneumothorax, moderate-severe nasal trauma, and bronchopulmonary dysplasia. MAIN RESULTS: We included 15 trials involving a total of 1437 infants. All trials were small (median number of participants 88). The methods used to generate the randomisation sequence and ensure allocation concealment were unclear in about half of the trial reports. Lack of measures to blind caregivers or investigators was a potential source of bias in all of the included trials. The trials took place during the past 25 years in care facilities internationally, predominantly in India (five trials) and Iran (four trials). The studied pressure sources were commercially available bubble CPAP devices versus a variety of mechanical ventilator (11 trials) or Infant Flow Driver (4 trials) devices.  Meta-analyses suggest that the use of bubble CPAP compared with mechanical ventilator or Infant Flow Driver CPAP may reduce the rate of treatment failure (RR 0.76, 95% confidence interval (CI) 0.60 to 0.95; (I² = 31%); RD -0.05, 95% CI -0.10 to -0.01; number needed to treat for an additional beneficial outcome 20, 95% CI 10 to 100; 13 trials, 1230 infants; low certainty evidence). The type of pressure source may not affect mortality prior to hospital discharge (RR 0.93, 95% CI 0.64 to 1.36 (I² = 0%); RD -0.01, 95% CI -0.04 to 0.02; 10 trials, 1189 infants; low certainty evidence). No data were available on neurodevelopmental impairment. Meta-analysis suggests that the pressure source may not affect the risk of pneumothorax (RR 0.73, 95% CI 0.40 to 1.34 (I² = 0%); RD -0.01, 95% CI -0.03 to 0.01; 14 trials, 1340 infants; low certainty evidence). Bubble CPAP likely increases the risk of moderate-severe nasal injury (RR 2.29, 95% CI 1.37 to 3.82 (I² = 17%); RD 0.07, 95% CI 0.03 to 0.11; number needed to treat for an additional harmful outcome 14, 95% CI 9 to 33; 8 trials, 753 infants; moderate certainty evidence). The pressure source may not affect the risk of bronchopulmonary dysplasia (RR 0.76, 95% CI 0.53 to 1.10 (I² = 0%); RD -0.04, 95% CI -0.09 to 0.01; 7 trials, 603 infants; low certainty evidence).  AUTHORS' CONCLUSIONS: Given the low level of certainty about the effects of bubble CPAP versus other pressure sources on the risk of treatment failure and most associated morbidity and mortality for preterm infants, further large, high-quality trials are needed to provide evidence of sufficient validity and applicability to inform context- and setting-relevant policy and practice.

Regional perspectives on the coordination and delivery of paediatric end-of-life care in the UK: a qualitative study.

BACKGROUND: Provision of and access to paediatric end-of-life care is inequitable, but previous research on this area has focused on perspectives of health professionals in specific settings or children with specific conditions. This qualitative study aimed to explore regional perspectives of the successes, and challenges to the equitable coordination and delivery of end-of-life care for children in the UK. The study provides an overarching perspective on the challenges of delivering and coordinating end-of-life care for children in the UK, and the impact of these on health professionals and organisations. Previous research has not highlighted the successes in the sector, such as the formal and informal coordination of care between different services and sectors. METHODS: Semi-structured interviews with Chairs of the regional Palliative Care Networks across the UK. Chairs or co-Chairs (n = 19) of 15/16 Networks were interviewed between October-December 2021. Data were analysed using thematic analysis. RESULTS: Three main themes were identified: one standalone theme ("Communication during end-of-life care"); and two overarching themes ("Getting end-of-life services and staff in the right place", with two themes: "Access to, and staffing of end-of-life care" and "Inconsistent and insufficient funding for end-of-life care services"; and "Linking up healthcare provision", with three sub-themes: "Coordination successes", "Role of the networks", and "Coordination challenges"). Good end-of-life care was facilitated through collaborative and network approaches to service provision, and effective communication with families. The implementation of 24/7 advice lines and the formalisation of joint-working arrangements were highlighted as a way to address the current challenges in the specialism. CONCLUSIONS: Findings demonstrate how informal and formal relationships between organisations and individuals, enabled early communication with families, and collaborative working with specialist services. Formalising these could increase knowledge and awareness of end of life care, improve staff confidence, and overall improve professionals' experiences of delivering care, and families' experiences of receiving it. There are considerable positives that come from collaborative working between different organisations and sectors, and care could be improved if these approaches are funded and formalised. There needs to be consistent funding for paediatric palliative care and there is a clear need for education and training to improve staff knowledge and confidence.

Use of induction of labour and emergency caesarean section and perinatal outcomes in English maternity services: a national hospital-level study.

OBJECTIVES: To assess the association between hospital-level rates of induction of labour and emergency caesarean section, as measures of "practice style", and rates of adverse perinatal outcomes. DESIGN: National study using electronic maternity records. SETTING: English National Health Service. PARTICIPANTS: Hospitals providing maternity care to women between April 2015 and March 2017. MAIN OUTCOME MEASURES: Stillbirth, admission to a neonatal unit, and babies receiving mechanical ventilation. RESULTS: Among singleton term births, the risk of stillbirth was 0.15%; of admission to a neonatal unit 5.4%; and of mechanical ventilation 0.54%. There was considerable between-hospital variation in the induction of labour rate (minimum 17.5%, maximum 40.7%) and the emergency caesarean section rate (minimum 5.6%, maximum 17.1%). Women who gave birth in hospitals with a higher induction of labour rate had better perinatal outcomes. For each 5%-point increase in induction, there was a decrease in the risk of term stillbirth by 9% (OR 0.91; 95% CI 0.85 to 0.97) and mechanical ventilation by 14% (OR 0.86; 95% CI 0.79 to 0.94). There was no significant association between hospital-level induction of labour rates and neonatal unit admission at term (p>0.05). There was no significant association between hospital-level emergency caesarean section rates and adverse perinatal outcomes (p always >0.05). CONCLUSIONS: There is considerable between-hospital variation in the use of induction of labour and emergency caesarean section. Hospitals with a higher induction rate had a lower risk of adverse birth outcomes. A similar association was not found for caesarean section.

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: Enteral feeding for very preterm or very low birth weight (VLBW) infants is often delayed for several days after birth due to concern that early introduction of feeding may not be tolerated and may increase the risk of necrotising enterocolitis. Concerns exist, however, that delaying enteral feeding may diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. OBJECTIVES: To determine the effects of delayed introduction of progressive enteral feeds on the risk of necrotising enterocolitis, mortality and other morbidities in very preterm or VLBW infants. SEARCH METHODS: Search strategies were developed by an information specialist in consultation with the review authors. The following databases were searched in October 2021 without date or language restrictions: CENTRAL (2021, Issue 10), MEDLINE via OVID (1946 to October 2021), Embase via OVID (1974 to October 2021), Maternity and Infant Care via OVID (1971 to October 2021), CINAHL (1982 to October 2021). We also searched for eligible trials in clinical trials databases, conference proceedings, previous reviews, and reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials that assessed the effects of delayed (four or more days after birth) versus earlier introduction of progressive enteral feeds on necrotising enterocolitis, mortality and other morbidities in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors separately evaluated trial risk of bias, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on necrotising enterocolitis, mortality,  feed intolerance, and invasive infection. MAIN RESULTS: We included 14 trials in which a total of 1551 infants participated. Potential sources of bias were lack of clarity on methods to generate random sequences and conceal allocation in half of the trials, and lack of masking of caregivers or investigators in all of the trials. Trials typically defined delayed introduction of progressive enteral feeds as later than four to seven days after birth and early introduction as four days or fewer after birth. Infants in six trials (accounting for about half of all of the participants) had intrauterine growth restriction or circulatory redistribution demonstrated by absent or reversed end-diastolic flow velocities in the fetal aorta or umbilical artery.  Meta-analyses showed that delayed introduction of progressive enteral feeds may not reduce the risk of necrotising enterocolitis (RR 0.81, 95% confidence interval (CI) 0.58 to 1.14; RD -0.02, 95% CI -0.04 to 0.01; 13 trials, 1507 infants; low-certainty evidence due risk of bias and imprecision) nor all-cause mortality before hospital discharge (RR 0.97, 95% CI 0.70 to 1.36; RD -0.00, 95% CI -0.03 to 0.03; 12 trials, 1399 infants; low-certainty evidence due risk of bias and imprecision). Delayed introduction of progressive enteral feeds may slightly reduce the risk of feed intolerance (RR 0.81, 95% CI 0.68 to 0.97; RD -0.09, 95% CI -0.17 to -0.02; number needed to treat for an additional beneficial outcome = 11, 95% CI 6 to 50; 6 trials, 581 infants; low-certainty evidence due to risk of bias and imprecision) and probably increases the risk of invasive infection (RR 1.44, 95% CI 1.15 to 1.80; RD 0.10, 95% CI 0.04 to 0.15; number needed to treat for a harmful outcome = 10, 95% CI 7 to 25; 7 trials, 872 infants; moderate-certainty evidence due to risk of bias).  AUTHORS' CONCLUSIONS: Delaying the introduction of progressive enteral feeds beyond four days after birth (compared with earlier introduction) may not reduce the risk of necrotising enterocolitis or death in very preterm or VLBW infants. Delayed introduction may slightly reduce feed intolerance, and probably increases the risk of invasive infection.

Synbiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with synbiotics (probiotic micro-organisms combined with prebiotic oligosaccharides) to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity. OBJECTIVES: To assess the effect of enteral supplementation with synbiotics (versus placebo or no treatment, or versus probiotics or prebiotics alone) for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Maternity and Infant Care database and CINAHL, from earliest records to 17 June 2021. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing prophylactic synbiotics supplementation with placebo or no synbiotics in very preterm (< 32 weeks' gestation) or very low birth weight (< 1500 g) infants. DATA COLLECTION AND ANALYSIS: Two review authors separately performed the screening and selection process,  evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference, with associated 95% confidence intervals (CIs). We used the GRADE approach to assess the level of certainty for effects on NEC, all-cause mortality, late-onset invasive infection, and neurodevelopmental impairment. MAIN RESULTS: We included six trials in which a total of 925 infants participated. Most trials were small (median sample size 200). Lack of clarity on methods used to conceal allocation and mask caregivers or investigators were potential sources of bias in four of the trials. The studied synbiotics preparations contained lactobacilli or bifidobacteria (or both) combined with fructo- or galacto-oligosaccharides (or both).  Meta-analyses suggested that synbiotics may reduce the risk of NEC (RR 0.18, 95% CI 0.09 to 0.40; RD 70 fewer per 1000, 95% CI 100 fewer to 40 fewer; number needed to treat for an additional beneficial outcome (NNTB) 14, 95% CI 10 to 25; six trials (907 infants); low certainty evidence); and all-cause mortality prior to hospital discharge (RR 0.53, 95% CI 0.33 to 0.85; RD 50 fewer per 1000, 95% CI 120 fewer to 100 fewer; NNTB 20, 95% CI 8 to 100; six trials (925 infants); low-certainty evidence). Synbiotics may have little or no effect on late-onset invasive infection, but the evidence is very uncertain (RR 0.84, 95% CI 0.58 to 1.21; RD 20 fewer per 1000, 95% CI 70 fewer to 30 more; five trials (707 infants); very low-certainty evidence). None of the trials assessed neurodevelopmental outcomes. In the absence of high levels of heterogeneity, we did not undertake any subgroup analysis (including the type of feeding). AUTHORS' CONCLUSIONS: The available trial data provide only low-certainty evidence about the effects of synbiotics on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants. Our confidence in the effect estimates is limited; the true effects may be substantially different from these estimates. Large, high-quality trials would be needed to provide evidence of sufficient validity and applicability to inform policy and practice.

Masks versus prongs as interfaces for nasal continuous positive airway pressure in preterm infants.

BACKGROUND: Nasal masks and nasal prongs are used as interfaces for providing continuous positive airway pressure (CPAP) for preterm infants with or at risk of respiratory distress, either as primary support after birth or as ongoing support after endotracheal extubation from mechanical ventilation. It is unclear which type of interface is associated with lower rates of CPAP treatment failure, nasal trauma, or mortality and other morbidity. OBJECTIVES: To assess the benefits and harms of nasal masks versus nasal prongs for reducing CPAP treatment failure, nasal trauma, or mortality and other morbidity in newborn preterm infants with or at risk of respiratory distress. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was October 2021. SELECTION CRITERIA: We included randomised controlled trials comparing masks versus prongs as interfaces for delivery of nasal CPAP in newborn preterm infants (less than 37 weeks' gestation) with or at risk of respiratory distress. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. treatment failure, 2. all-cause mortality, and 3. neurodevelopmental impairment. Our secondary outcomes were 4. pneumothorax, 5. moderate-severe nasal trauma, 6. bronchopulmonary dysplasia, 7. duration of CPAP use, 8. duration of oxygen supplementation, 9. duration of hospitalisation, 10. patent ductus arteriosus receiving medical or surgical treatment, 11. necrotising enterocolitis, 12. severe intraventricular haemorrhage, and 13. severe retinopathy of prematurity. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 12 trials with 1604 infants. All trials were small (median number of participants 118). The trials occurred after 2001 in care facilities internationally, predominantly in India (eight trials). Most participants were preterm infants of 26 to 34 weeks' gestation who received nasal CPAP as the primary form of respiratory support after birth. The studied interfaces included commonly used commercially available masks and prongs. Lack of measures to blind caregivers or investigators was a potential source of performance and detection bias in all the trials. Meta-analyses suggested that use of masks compared with prongs may reduce CPAP treatment failure (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.90; 8 trials, 919 infants; low certainty). The type of interface may not affect mortality prior to hospital discharge (RR 0.83, 95% CI 0.56 to 1.22; 7 trials, 814 infants; low certainty). There are no data on neurodevelopmental impairment. Meta-analyses suggest that the choice of interface may result in little or no difference in the risk of pneumothorax (RR 0.93, 95% CI 0.45 to 1.93; 5 trials, 625 infants; low certainty). Use of masks rather than prongs may reduce the risk of moderate-severe nasal injury (RR 0.55, 95% CI 0.44 to 0.71; 10 trials, 1058 infants; low certainty). The evidence is very uncertain about the effect on bronchopulmonary dysplasia (RR 0.69, 95% CI 0.46 to 1.03; 7 trials, 843 infants; very low certainty). AUTHORS' CONCLUSIONS: The available trial data provide low-certainty evidence that use of masks compared with prongs as the nasal CPAP interface may reduce treatment failure and nasal injury, and may have little or no effect on mortality or the risk of pneumothorax in newborn preterm infants with or at risk of respiratory distress. The effect on bronchopulmonary dysplasia is very uncertain. Large, high-quality trials would be needed to provide evidence of sufficient validity and applicability to inform policy and practice.

Evidence for causal associations between prenatal and postnatal antibiotic exposure and asthma in children, England.

BACKGROUND: Higher risks of asthma have been observed in children with prenatal exposure to antibiotics and during early life compared with those who have not. However, the causality of such associations is unclear. OBJECTIVE: To assess whether exposure to antibiotics in early life had a causal effect in increasing the risk of asthma in children diagnosed at 5-8 years of life, and the impact in the target population. METHODS: Data were from electronic health records and questionnaires for children and their mothers in the Born in Bradford birth cohort. Exposure variables were prescriptions of systemic antibiotics to the mother during pregnancy (prenatal) and to the children at 0-24 months of life (postnatal). We assessed the association in 12,476 children with several approaches to deal with different sources of bias (triangulation): the interactions with mother's ethnicity, mode of delivery, and between prenatal and postnatal exposures; dose-response; and estimated the population attributable risk. RESULTS: There was an association between prenatal exposure at 7-27 days before the child's birth and asthma (adjusted OR = 1.40; 1.05, 1.87), but no association with the negative control exposure (before pregnancy) (adjusted OR = 0.99 (0.88, 1.12)). For postnatal exposure, the adjusted OR was 2.00 (1.71, 2.34), and for sibling analysis, it was 1.99 (1.00, 3.93). For postnatal exposure, the risk of asthma increased with the number of prescriptions. The observed effect of both exposures was lower among children with mothers of Pakistani ethnicity, but inconclusive (p > .25). The interaction between prenatal and postnatal exposures was also inconclusive (p = .287). The population attributable risk of postnatal exposure for asthma was 4.6% (0.1% for prenatal). CONCLUSIONS: We conclude that the associations between both late-pregnancy prenatal exposure to antibiotics and postnatal exposure to antibiotics and an increased risk of asthma are plausible and consistent with a causal effect.

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of NEC. However, it is unclear whether slow feed advancement may delay establishment of full enteral feeding, and if it could be associated with infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine the effects of slow rates of enteral feed advancement on the risk of NEC, mortality, and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We searched CENTRAL (2020, Issue 10), Ovid MEDLINE (1946 to October 2020), Embase via Ovid (1974 to October 2020), Maternity and Infant Care database (MIDIRS) (1971 to October 2020), CINAHL (1982 to October 2020), and clinical trials databases and reference lists of retrieved articles for eligible trials. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials that assessed effects of slow (up to 24 mL/kg/d) versus faster rates of advancement of enteral feed volumes on the risk of NEC in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors separately evaluated trial risk of bias, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence. Outcomes of interest were NEC, all-cause mortality, feed intolerance, and invasive infection. MAIN RESULTS: We included 14 trials involving a total of 4033 infants (2804 infants participated in one large trial). None of the trials masked parents, caregivers, or investigators. Risk of bias was otherwise low. Most infants were stable very preterm or VLBW infants of birth weight appropriate for gestation. About one-third of all infants were extremely preterm or extremely low birth weight (ELBW), and about one-fifth were small for gestational age, growth-restricted, or compromised as indicated by absent or reversed end-diastolic flow velocity in the foetal umbilical artery. Trials typically defined slow advancement as daily increments of 15 to 24 mL/kg, and faster advancement as daily increments of 30 to 40 mL/kg. Meta-analyses showed that slow advancement of enteral feed volumes probably has little or no effect on the risk of NEC (RR 1.06, 95% confidence interval (CI) 0.83 to 1.37; RD 0.00, 95% CI -0.01 to 0.02; 14 trials, 4026 infants; moderate-certainty evidence) or all-cause mortality prior to hospital discharge (RR 1.13, 95% CI 0.91 to 1.39; RD 0.01, 95% CI -0.01 to 0.02; 13 trials, 3860 infants; moderate-certainty evidence). Meta-analyses suggested that slow advancement may slightly increase feed intolerance (RR 1.18, 95% CI 0.95 to 1.46; RD 0.05, 95% CI -0.02 to 0.12; 9 trials, 719 infants; low-certainty evidence) and may slightly increase the risk of invasive infection (RR 1.14, 95% CI 0.99 to 1.31; RD 0.02, 95% CI -0.00 to 0.05; 11 trials, 3583 infants; low-certainty evidence). AUTHORS' CONCLUSIONS: The available trial data indicate that advancing enteral feed volumes slowly (daily increments up to 24 mL/kg) compared with faster rates probably does not reduce the risk of NEC, death, or feed intolerance in very preterm or VLBW infants. Advancing the volume of enteral feeds at a slow rate may slightly increase the risk of invasive infection.

Early full enteral feeding for preterm or low birth weight infants.

BACKGROUND: The introduction and advancement of enteral feeds for preterm or low birth weight infants is often delayed because of concerns that early full enteral feeding will not be well tolerated or may increase the risk of necrotising enterocolitis. Early full enteral feeding, however, might increase nutrient intake and growth rates; accelerate intestinal physiological, metabolic, and microbiomic postnatal transition; and reduce the risk of complications associated with intravascular devices for fluid administration.  OBJECTIVES: To determine how early full enteral feeding, compared with delayed or progressive introduction of enteral feeds, affects growth and adverse events such as necrotising enterocolitis, in preterm or low birth weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials; MEDLINE Ovid, Embase Ovid, Maternity & Infant Care Database Ovid, the Cumulative Index to Nursing and Allied Health Literature, and clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials to October 2020. SELECTION CRITERIA: Randomised controlled trials that compared early full enteral feeding with delayed or progressive introduction of enteral feeds in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. Two review authors separately assessed trial eligibility, evaluated trial quality, extracted data, and synthesised effect estimates using risk ratios (RR), risk differences, and mean differences (MD) with 95% confidence intervals (CI). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included six trials. All were undertaken in the 2010s in neonatal care facilities in India. In total, 526 infants participated. Most were very preterm infants of birth weight between 1000 g and 1500 g. Trials were of good methodological quality, but a potential source of bias was that parents, clinicians, and investigators were not masked. The trials compared early full feeding (60 mL/kg to 80 mL/kg on day one after birth) with minimal enteral feeding (typically 20 mL/kg on day one) supplemented with intravenous fluids. Feed volumes were advanced daily as tolerated by 20 mL/kg to 30 mL/kg body weight to a target steady-state volume of 150 mL/kg to 180 mL/kg/day. All participating infants were fed preferentially with maternal expressed breast milk, with two trials supplementing insufficient volumes with donor breast milk and four supplementing with preterm formula.  Few data were available to assess growth parameters. One trial (64 participants) reported a slower rate of weight gain (median difference -3.0 g/kg/day), and another (180 participants) reported a faster rate of weight gain in the early full enteral feeding group (MD 1.2 g/kg/day). We did not meta-analyse these data (very low-certainty evidence). None of the trials reported rate of head circumference growth. One trial reported that the mean z-score for weight at hospital discharge was higher in the early full enteral feeding group (MD 0.24, 95% CI 0.06 to 0.42; low-certainty evidence). Meta-analyses showed no evidence of an effect on necrotising enterocolitis (RR 0.98, 95% CI 0.38 to 2.54; 6 trials, 522 participants; I² = 51%; very low-certainty evidence). AUTHORS' CONCLUSIONS: Trials provided insufficient data to determine with any certainty how early full enteral feeding, compared with delayed or progressive introduction of enteral feeds, affects growth in preterm or low birth weight infants. We are uncertain whether early full enteral feeding affects the risk of necrotising enterocolitis because of the risk of bias in the trials (due to lack of masking), inconsistency, and imprecision.

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity.  OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 2) in the Cochrane Library; MEDLINE Ovid (1946 to 17 Feb 2020), Embase Ovid (1974 to 17 Feb 2020), Maternity & Infant Care Database Ovid (1971 to 17 Feb 2020), the Cumulative Index to Nursing and Allied Health Literature (1982 to 18 Feb 2020). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs and quasi-RCTs comparing probiotic supplementation with placebo or no probiotics in very preterm or very low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on NEC, all-cause mortality, late-onset infection, and severe neurodevelopmental impairment. MAIN RESULTS: We included 56 trials in which 10,812 infants participated. Most trials were small (median sample size 149). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were the main potential sources of bias in about half of the trials. Trials varied by the formulation of the probiotics. The most commonly used preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., and Streptococcus spp. alone or in combinations. Meta-analysis showed that probiotics may reduce the risk of NEC: RR 0.54, 95% CI 0.45 to 0.65 (54 trials, 10,604 infants; I² = 17%); RD -0.03, 95% CI -0.04 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 25 to 50. Evidence was assessed as low certainty because of the limitations in trials design, and the presence of funnel plot asymmetry consistent with publication bias. Sensitivity meta-analysis of trials at low risk of bias showed a reduced risk of NEC: RR 0.70, 95% CI 0.55 to 0.89 (16 trials, 4597 infants; I² = 25%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100. Meta-analyses showed that probiotics probably reduce mortality (RR 0.76, 95% CI 0.65 to 0.89; (51 trials, 10,170 infants; I² = 0%); RD -0.02, 95% CI -0.02 to -0.01; NNTB 50, 95% CI 50 to 100), and late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; (47 trials, 9762 infants; I² = 19%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100). Evidence was assessed as moderate certainty for both these outcomes because of the limitations in trials design. Sensitivity meta-analyses of 16 trials (4597 infants) at low risk of bias did not show an effect on mortality or infection. Meta-analysis showed that probiotics may have little or no effect on severe neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26 (five trials, 1518 infants; I² = 0%). The certainty on this evidence is low because of limitations in trials design and serious imprecision of effect estimate. Few data (from seven of the trials) were available for extremely preterm or extremely low birth weight infants. Meta-analyses did not show effects on NEC, death, or infection (low-certainty evidence). AUTHORS' CONCLUSIONS: Given the low to moderate level of certainty about the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants, and particularly for extremely preterm or extremely low birth weight infants, further, large, high-quality trials are needed to provide evidence of sufficient quality and applicability to inform policy and practice.

Treating extravasation injuries in infants and young children: a scoping review and survey of UK NHS practice.

BACKGROUND: Extravasation injuries are caused by unintended leakages of fluids or medicines from intravenous lines but there is no consensus on the best treatment approaches, particularly in infants and young children. METHODS: This paper presents a more succinct account of a study of treatments for extravasation injuries in infants and children which has also been reported in full as an NIHR HTA report. A systematic scoping review and survey of UK NHS practice were undertaken. Twelve databases - including MEDLINE and EMBASE - were searched for relevant studies in February 2017. Studies of children with extravasation injuries receiving any treatment for extravasation injury were eligible, providing they reported one of the following outcomes: wound healing time, infection, pain, scarring, functional impairment, and requirement for surgery. Studies were screened in duplicate. Data were extracted by one researcher and checked by another. Studies were summarised narratively. An online questionnaire was distributed to NHS staff at neonatal units, paediatric intensive care units and principal oncology/haematology units. RESULTS: The evidence identified in the scoping review was mostly comprised of small, retrospective, uncontrolled group studies or case reports. The studies covered a wide range of interventions including conservative management approaches, saline flush-out techniques (with or without prior hyaluronidase), hyaluronidase without flush-out, artificial skin treatments, debridement and plastic surgery. Few studies graded injury severity and the results sections and outcomes reported in most studies were limited. There was heterogeneity across study populations in many factors. The survey yielded 63 responses from hospital units across the UK. Results indicated that although most units had written documentation for treating extravasation injuries, only one-third of documents included a system for grading injury severity. The most frequently used interventions were elevation of the affected area and analgesics. Saline wash-out treatments, either with or without hyaluronidase, were regularly used in about half of all neonatal units. Most responders thought a randomised controlled trial might be a viable future research design. CONCLUSIONS: There is some uncertainty about which are most the promising treatments for extravasation injuries in infants and young children. Saline flush-out techniques and conservative management approaches are commonly used and may be suitable for evaluation in trials. Although conventional randomised trials may be difficult to perform a randomised registry trial may be an appropriate alternative design.

Newborn Length of Stay and Risk of Readmission.

BACKGROUND: Evidence on the association between newborn length of hospital stay (LOS) and risk of readmission is conflicting. We compared methods for modelling this relationship, by gestational age, using population-level hospital data on births in England between 2005-14. METHODS: The association between LOS and unplanned readmission within 30 days of postnatal discharge was explored using four approaches: (i) modelling hospital-level LOS and readmission rates; (ii) comparing trends over time in LOS and readmission; (iii) modelling individual LOS and adjusted risk of readmission; and (iv) instrumental variable analyses (hospital-level mean LOS and number of births on the same day). RESULTS: Of 4 667 827 babies, 5.2% were readmitted within 30 days. Aggregated data showed hospitals with longer mean LOS were not associated with lower readmission rates for vaginal (adjusted risk ratio (aRR) 0.87, 95% confidence interval (CI) 0.66, 1.13), or caesarean (aRR 0.89, 95% CI 0.72, 1.12) births. LOS fell by an average 2.0% per year for vaginal births and 3.4% for caesarean births, while readmission rates increased by 4.4 and 5.1% per year respectively. Approaches (iii) and (iv) indicated that longer LOS was associated with a reduced risk of readmission, but only for late preterm, vaginal births (34-36 completed weeks' gestation). CONCLUSIONS: Longer newborn LOS may benefit late preterm babies, possibly due to increased medical or psychosocial support for those at greater risk of potentially preventable readmissions after birth. Research based on observational data to evaluate relationships between LOS and readmission should use methods to reduce the impact of unmeasured confounding.

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of NEC. However, slow feed advancement may delay establishment of full enteral feeding and may be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine effects of slow rates of enteral feed advancement on the incidence of NEC, mortality, and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We used the standard Cochrane Neonatal search strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 5), MEDLINE via PubMed (1966 to June 2017), Embase (1980 to June 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to June 2017). We searched clinical trials databases, conference proceedings, previous reviews, and reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed effects of slow (up to 24 mL/kg/d) versus faster rates of advancement of enteral feed volumes upon the incidence of NEC in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported risk ratio (RR) and risk difference (RD) for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model for meta-analyses and explored potential causes of heterogeneity via sensitivity analyses. We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified 10 RCTs in which a total of 3753 infants participated (2804 infants participated in one large trial). Most participants were stable very preterm infants of birth weight appropriate for gestation. About one-third of all participants were extremely preterm or extremely low birth weight (ELBW), and about one-fifth were small for gestational age (SGA), growth-restricted, or compromised in utero, as indicated by absent or reversed end-diastolic flow velocity (AREDFV) in the fetal umbilical artery. Trials typically defined slow advancement as daily increments of 15 to 20 mL/kg, and faster advancement as daily increments of 30 to 40 mL/kg. Trials generally were of good methodological quality, although none was blinded.Meta-analyses did not show effects on risk of NEC (typical RR 1.07, 95% CI 0.83 to 1.39; RD 0.0, 95% CI -0.01 to 0.02) or all-cause mortality (typical RR 1.15, 95% CI 0.93 to 1.42; typical RD 0.01, 95% CI -0.01 to 0.03). Subgroup analyses of extremely preterm or ELBW infants, or of SGA or growth-restricted or growth-compromised infants, showed no evidence of an effect on risk of NEC or death. Slow feed advancement delayed establishment of full enteral nutrition by between about one and five days. Meta-analysis showed borderline increased risk of invasive infection (typical RR 1.15, 95% CI 1.00 to 1.32; typical RD 0.03, 95% CI 0.00 to 0.05). The GRADE quality of evidence for primary outcomes was "moderate", downgraded from "high" because of lack of blinding in the included trials. AUTHORS' CONCLUSIONS: Available trial data do not provide evidence that advancing enteral feed volumes at daily increments of 15 to 20 mL/kg (compared with 30 to 40 mL/kg) reduces the risk of NEC or death in very preterm or VLBW infants, extremely preterm or ELBW infants, SGA or growth-restricted infants, or infants with antenatal AREDFV. Advancing the volume of enteral feeds at a slow rate results in several days of delay in establishing full enteral feeds and may increase the risk of invasive infection.