Chris Gale

Objective: To examine the association between prophylactic hydrocortisone, given to prevent bronchopulmonary dysplasia, and the risk of focal intestinal perforation (FIP) in preterm infants. Design: Retrospective cohort study using routinely-collected data from infants born between 2016 and 2023. Setting: All English and Welsh neonatal units. Patients: 15 746 infants born at less than 28 weeks gestation and admitted to a neonatal unit. Infants were matched (exposed vs unexposed) using a propensity score comprising 17 variables. Exposure: Exposed infants received hydrocortisone for at least eight consecutive days beginning on postnatal day one or two. Unexposed infants did not receive hydrocortisone in line with this definition. Main outcome measures: Primary outcome was FIP. Secondary outcomes included mortality, survival without FIP, bronchopulmonary dysplasia. Results: 6.3% (999/15 746) infants were exposed to early hydrocortisone and 4.6% (722/15 746) had FIP. 2815 infants (988 exposed and 1827 unexposed) were included in the matched analysis; 47% girls, median gestational age of 26.0 weeks (IQR 24.6–26.9) and median birth weight of 815 g (IQR 674–965). There was no significant difference in risk of FIP (4.9% (48/988) exposed vs 6.1% (111/1827) unexposed, OR 0.79, 95% CI 0.55 to 1.14); findings were consistent in the sensitivity analyses. Early hydrocortisone was associated with increased mortality (21.3% (210/988) exposed vs 16.2% (295/1827) unexposed, OR 1.40, 95% CI 1.14 to 1.72). Conclusions: Early prophylactic hydrocortisone from the first postnatal week was not associated with FIP. The observed association with higher mortality was a secondary finding in this observational study and requires cautious interpretation and further investigation.

Iron deficiency anaemia (IDA) affects up to 30% of all pregnant women often causing symptoms including malaise and lethargy which can significantly impact daily life and well-being. Additionally, IDA is associated with serious complications, including an increased risk of bleeding, preterm birth, small for gestational age babies and rarely, but significantly, stillbirth. The most common current management approach reactively treats IDA once it is diagnosed, usually with an oral iron preparation such as ferrous sulphate or another ferrous salt. There have been calls to investigate a policy of prevention, to discover if outcomes can be improved. We therefore designed the primary prevention of maternal anaemia to prevent preterm delivery and other adverse outcomes trial, to assess whether the prevention of IDA during pregnancy, through routine iron supplementation from early pregnancy, will reduce the risks of significant adverse clinical outcomes for women and their babies. Design: Randomised, double-blind, placebo-controlled trial to evaluate the effectiveness of low-dose ferrous sulfate in the primary prevention of IDA, alongside an intervention to support medication adherence, with a parallel process evaluation to explore acceptability, fidelity and mechanisms of action. Participants: 11 020 women in their first trimester of pregnancy, who are not anaemic and have no contraindication to oral iron, will be recruited from maternity units. Intervention: A tablet of ferrous sulfate 200 mg (65 mg of elemental iron) once daily compared with an identically matched placebo tablet, administered from recruitment in the first trimester (anytime ≤15 weeks+6 days gestation) through until 6 weeks post partum or when all of the tablets have been taken, whichever is sooner. Participants are supplied with a total of 240 tablets to cover the whole period of the study. An adherence intervention to support initiation and adherence to iron supplementation was also delivered. Outcomes: The primary outcome is a composite of preterm birth, small for gestational age, stillbirth and neonatal death. Secondary outcomes include development of maternal anaemia, post-partum haemorrhage, postnatal depression, breast feeding rates, quality of life scores, and in the neonate admissions to a higher level of care and early-onset infection. Long-term offspring neurodevelopmental follow-up will continue beyond this period. This study will establish the clinical and cost-effectiveness of universal oral iron supplementation in pregnancy. ( ISRCTN16425597 )

In children with SRS (patients), does initiation of recombinant GH therapy before 4 years of age (intervention) result in greater improvements in height and cardiometabolic outcomes (outcome) compared with initiation at 4 years or later (comparison)?

Background: Clustering of outcomes occurs naturally in neonatal data due to multiple births clustered by mother and infants clustered within the neonatal unit administering their care. Estimating these cluster effects is important for neonatal study design and impacts upon sample sizes for neonatal trials. Methods: We analysed retrospective data from all neonatal admissions in England and Wales between January 2016 and January 2020 held in the National Neonatal Research Database. Intracluster correlation coefficients (ICCs) and their 95% confidence intervals were calculated for core neonatal outcomes and those commonly used in trials, at the level of both the neonatal unit and mother. Results were stratified by gestational age and neonatal unit level of birth. To illustrate the impact of clustering, the design effect was estimated for a theoretical cluster trial. Results: Intracluster correlation coefficients varied between outcomes and gestational age groups. Neonatal unit level intracluster correlation coefficients were low for mortality (0.0054, 95% CI 0.0039, 0.0068) and other core outcomes (severe necrotising enterocolitis 0.0042, 95% CI 0.0020, 0.0063) and were higher for outcomes related to care delivery (duration of intensive care 0.0237, 95% CI 0.0177, 0.0298; duration receiving parenteral nutrition 0.0265, 95% CI 0.0197, 0.0332). Gestation at birth was inversely correlated with neonatal unit ICC estimates. At the level of the mother, ICC estimates were generally larger, especially for preterm infants. Conclusions: We have estimated ICCs for key neonatal outcomes at the level of both neonatal unit and mother with high precision using national, population-level routinely recorded data. These ICC estimates can be used to inform future neonatal studies and sample size calculations for neonatal trials.

Objective To assess regional and temporal variation and influencing factors of low-grade intraventricular haemorrhage (IVH) incidence among preterm infants admitted to neonatal units in England. Design Population cohort study Setting England, UK. Patients All infants born Event Low-grade IVH (grade 1–2). Main outcome measures Crude incidence rates and adjusted incidence rate ratios (IRRs) from Poisson models comparing calendar years, geographically defined operational delivery networks, sex and gestation. Results Low-grade IVH occurred in 8.7% (14 415/165 269) of preterm admissions. Crude incidence increased from 6.8% in 2008–2009 to 10.1% in 2018–2019. After adjustment for gestation, sex and neonatal network, incidence in 2018–2019 was higher than in 2008–2009 (adjusted IRR 1.64, 95% CI 1.51 to 1.79). Both grade 1 and grade 2 IVH rose over time. Geographical heterogeneity was pronounced: low-grade IVH incidence ranged from 2.6% to 15.9% across networks, a more than sixfold difference that persisted after case-mix adjustment. Temporal patterns also diverged by network, some showed high and rising incidence over time, while others remained lower or stable. Conclusion Low-grade IVH is common among preterm admissions and recorded incidence increased between 2008 and 2019, with consistent gestational and sex patterns and substantial geographical variation. The contribution of interobserver diagnostic variability to this variation is unknown; nonetheless, the magnitude and consistency of the trends suggest a rising, potentially uneven burden of low-grade IVH in England, warranting further investigation to inform quality improvement interventions.

Randomised controlled trials that use cohorts or health-and-care systems data, often known as routinely collected data—such as electronic health records, registries, or administrative claims—are becoming increasingly common. These trials have the potential to streamline recruitment, intervention delivery, follow-up (within trial and long term), and to lower costs. The lack of clear information governance pathways, heterogeneous data quality, delays in data recording and acquisition, and regulatory or ethical complexities undermine reproducibility and bias assessment when routinely collected data are used in trials. We introduce the SPIRIT-ROUTINE extension to the SPIRIT 2025 guideline: a checklist and explanation designed to improve the reporting of trial protocols that rely on cohorts or routinely collected data sources. Investigators, funders, ethics committees, journal editors, and peer reviewers can use the SPIRIT-ROUTINE extension to enhance completeness, transparency, and usability of such protocols to support better research, healthcare decisions, and patient outcomes.

Aims: Co-existence of atrial cardiomyopathy (AtCM) and heart failure with reduced ejection fraction (HFrEF) has prognostic implications. We aimed to quantify the association of a health records data biomarker, FIND-AF, with outcomes in patients with HFrEF and AtCM without atrial fibrillation (AF). Methods: Patients with HFrEF and AtCM without AF at baseline were identified from the ECG-HF registry (2010–6) and linked to the territory-wide Clinical Data Analysis and Reporting System. AtCM was operationalized using a pragmatic multi-domain framework based on the 2025 clinical consensus statement of the Heart Failure Association of the ESC, using electrocardiographic and echocardiographic parameters. Patients were stratified into high and low risk by sex-specific FIND-AF thresholds. The primary outcome was a composite of incident AF, ischaemic stroke, and all-cause mortality. All patients were followed until 31 December 2019. Results: We included 164 patients (mean age 62.3 ± 13.0 years, 73.8% men). The primary outcome occurred in 23/32 (71.9%) high-risk vs 67/132 (50.8%) low-risk patients (OR 2.48, 95% CI 1.07–5.76; P = .035). In the model including both FIND-AF risk group and AtCM severity, high FIND-AF risk remained associated with the composite outcome (adjusted OR 2.70, 95% CI 1.14–6.40; P = .024). Compared with CHA2DS2-VASc, FIND-AF showed superior discrimination for the composite outcome (AUC .735 vs .641; DeLong P = .007) and ischaemic stroke (AUC .700 vs .575; DeLong P = .008). Conclusions: High FIND-AF risk is associated with adverse prognosis in a cohort of patients with HFrEF and AtCM but without baseline AF. These exploratory data require external validation and a prospective study.