OBJECTIVES:To describe haemolytic disease outcomes, growth, neurodevelopment and health-related quality of life (HRQoL) through 24 months of life in infants exposed to nipocalimab in pregnancies at high risk of early-onset severe haemolytic disease of the fetus and newborn (EOS-HDFN). DESIGN:A multicentre, open-label, single-arm trial. SETTING:Centres with expertise in HDFN management. PATIENTS:Pregnant individuals with previous EOS-HDFN and maternal anti-D titres ≥32 or anti-K titres ≥4. INTERVENTIONS:Weekly nipocalimab (30 and/or 45 mg/kg) from 14 to 35 gestational weeks. MAIN OUTCOME MEASURES:Infants' cord-blood alloantibody titres at birth, HDFN management, growth through 6 months, neurodevelopment (caregiver-reported Ages and Stages Questionnaire, third edition (ASQ-3)) and HRQoL assessments through 24 months of life. RESULTS:Of 13 pregnancies, 12 resulted in live births; one fetal loss occurred due to intrauterine transfusion (IUT) complications. A single simple transfusion was administered in one of seven infants delivered after a maternal nipocalimab course without IUTs, where cord blood alloantibody titres were <8. Multiple transfusions (one to seven simple transfusions/infant; one exchange transfusion) were administered to five infants delivered after early nipocalimab discontinuation and IUTs, with cord-blood alloantibody titres ranging from 512 to 32 768. No unusual growth patterns were observed through 6 months. No neurodevelopmental delays were identified through 24 months of life, with mean ASQ-3 domain scores within normal ranges. HRQoL outcomes were positive across physical, emotional, social and cognitive functioning. CONCLUSIONS:Maternal nipocalimab in pregnancies at high risk of EOS-HDFN may reduce adverse neonatal outcomes correlating with low cord-blood alloantibody titres, without affecting growth through 6 months, neurodevelopment or HRQoL through 24 months of life. TRIAL REGISTRATION NUMBER:NCT03842189.
OBJECTIVE:To evaluate neurodevelopmental outcomes at 2-3 years of age among survivors of extremely preterm infant (EPI). DESIGN AND SETTING:Analysis of prospectively collected Australian and New Zealand Neonatal Network data on infants born <28 weeks' gestation between 2010 and 2019. MAIN OUTCOME:The prevalence of neurodevelopmental impairment (NDI), defined as any moderate to severe cerebral palsy (CP), sensory impairment or developmental delay (score <70) at 2-3 years of age was determined. Epoch comparisons (2010-204 vs 2015-2019) and the impact of major morbidity on NDI were examined, adjusting for maternal age, antenatal steroids, gestational age, Apgar score, admission temperature, sex and breast milk feeding. RESULTS:Of 6617 EPIs, 15.5% had NDI. Developmental delay was most prevalent (14.5%), including language (11.1%), motor (5.9%), cognitive (5.7%) domains, followed by CP (3.2%), deafness (1.4%) and blindness (0.4%). Compared with infants without morbidity, adjusted odds of NDI increased with one (adjusted OR (aOR) 1.50, 95% CI 1.21 to 1.84), two (aOR 2.09, 95% CI 1.60 to 2.53) and three or more coexisting morbidities (aOR 3.56, 95% CI 2.73 to 4.65). Between epochs, bronchopulmonary dysplasia increased by 6.9% and retinopathy of prematurity by 3.8%, alongside a rise in developmental delay (10.3% to 17.8%), contributing to a 6.6% absolute increase in NDI. Survivors born at 22-23 weeks had the highest NDI rates, increasing from 23.0% to 26.4%. CONCLUSION:NDI rates among EPI increased over time and were associated with increasing multiple morbidities. Although changes in EPIs survival patterns may have contributed to these trends, reducing neonatal morbidities and strengthening neuroprotective care remain priorities.
OBJECTIVE:Breast milk is the optimal source of nutrition for preterm infants; however, low breast milk production is common following a preterm birth. This study aimed to determine if taking brewers' yeast or beta-glucan improves daily expressed breast milk volume. DESIGN:Randomised, blinded, parallel, placebo-controlled trial. SETTING:Three Australian tertiary-level neonatal units. PATIENTS:Mothers with a singleton or twin pregnancy who gave birth at <34 weeks' gestation. INTERVENTIONS:Mothers were randomised within 72 hours of birth into three parallel groups in a 1:1:1 ratio to receive either brewers' yeast, beta-glucan or placebo capsules for 7 days. MAIN OUTCOME MEASURE:Total expressed breast milk volume over a 24-hour period on day 7 of intervention. RESULTS:A total of 105 mothers underwent randomisation between August 2022 and April 2024 (36 brewers' yeast, 35 beta-glucan and 34 placebo). The adjusted mean difference in daily expressed breast milk volume was 94 mL/day (95% CI -51 mL/day to 239 mL/day) between the brewers' yeast and placebo groups and -25 mL/day (95% CI -173 mL/day to 123 mL/day) between the beta-glucan and placebo groups. Maternal side effects were similar across groups. CONCLUSION:We found no clear effect of short-term administration of brewers' yeast or beta-glucan on breast-milk production following preterm birth; both interventions were well tolerated. Given the small sample size, these findings do not rule out the possibility of a clinically meaningful benefit of brewers' yeast and suggest further research with a larger sample size may be warranted to clarify the potential clinical impact. TRIAL REGISTRATION NUMBER:ACTRN12622000968774.
OBJECTIVE:To explore the feasibility of a randomised controlled trial (RCT) of donor human milk (DHM) use for preterm infants with mother's own milk (MOM) shortfall, assessing DHM impact on breastfeeding. DESIGN:Feasibility, open-label RCT. SETTING:Two tertiary neonatal intensive care units in the UK. PATIENTS:135 infants born before 33 weeks' gestation or with birth weight <1500 g whose mothers intended to provide MOM admitted between June 2021 and March 2023. INTERVENTIONS:Infants were randomly assigned to either DHM for MOM shortfall until full feeds (FFs) and preterm formula thereafter, control (DHM-FF group) or the intervention, DHM until 36 weeks corrected gestational age (CGA) or discharge if sooner (DHM-36w group). MAIN OUTCOME MEASURES:Feasibility outcomes included study recruitment, retention and intervention feasibility measures. The primary clinical outcome was breastfeeding or receipt of any MOM at 36 weeks CGA or discharge if sooner. Secondary clinical outcomes included growth and neonatal morbidities. RESULTS:Of 325 screened infants, 247 were eligible, out of which 135 were recruited (54.7%). Parents of 36 infants declined DHM. Three infants discontinued DHM use during the study. 13 infants could not access the intervention due to transfer.38/66 (57.6%) infants from the DHM-FF group and 40/69 (58%) infants from the DHM-36w group received some MOM at 36 weeks' CGA. There were no significant differences between groups in growth and morbidity outcomes. CONCLUSIONS:The RCT design is feasible for future, larger-scale studies. Availability of MOM did not differ between groups at 36 weeks but was higher than historical cohorts. TRIAL REGISTRATION NUMBER:57339063.
BACKGROUND:Wheezing, a symptom reflecting bronchial obstruction, is frequently reported in preterm-born infants. No objective and reliable tool is available to assert this diagnosis with minimal patient cooperation. Nocturnal tidal breathing measurements by impedance pneumography (IP) provide expiratory variability index (EVI) and the ratio of time to peak tidal expiratory flow to total expiration (tPTEF/tE) which are reduced in bronchial obstruction and may address this gap. AIMS:To evaluate the application of IP measurements in a cohort of preterm-born infants. METHODS:Home measurements were performed over two consecutive nights in infants (median (IQR) gestational age 34+4 weeks (33+1; 35+2)), around ages 3, 6 and 12 months. EVI and tPTEF/tE were derived from successful recordings (≥4 hours undisturbed). Measurements in term-born infants <14 months served as reference. RESULTS:In total 372 night-recordings were obtained from 97 preterm infants. Success rates were 15%, 93% and 91% in infants aged <4 months, 4-9 months and >9 months, respectively. Explorative analyses showed EVI decreased during wheezing episodes from 14.4 (95% CI 13.2 to 15.7) to 9.6 (95% CI 5.6 to 13.5). Both EVI and tPTEF/tE tended to be lower in preterm than in term infants: EVI 14.6 (95% CI 13.5 to 15.8) versus 16.3 (95% CI 15.0 to 17.6) and tPTEF/tE 0.160 (95% CI 0.142 to 0.177) versus 0.187 (95% CI 0.158 to 0.216) CONCLUSIONS: Home IP measurement in preterm-born infants is moderately feasible, with improving success in older infants. Differences in EVI and tPTEF/tE by gestational maturity and during wheezing episodes indicate that IP provides clinically relevant information on airway obstruction, supporting its potential for research and future clinical use.
OBJECTIVE:To assess how restricting open-label access to an off-label drug influences consent and trial enrolment in neonatal medicine. DESIGN:Multicentre, quasinatural experiment. SETTING:Seventeen neonatal intensive care units in the Netherlands and Belgium participating in the DOXA-trial, a double-blind, randomised, placebo-controlled study of doxapram in extremely preterm infants. PATIENTS:Infants born before 29 weeks' gestation whose parents were approached for DOXA-trial participation. INTERVENTIONS:Ten centres discontinued open-label doxapram outside the DOXA-trial (intervention centres), while seven continued its use (control centres). MAIN OUTCOME MEASURES:Parental consent rates (proportion of parents who provided written informed consent among those approached) and patient enrolment rates (proportion of infants randomised among those whose parents were approached), compared 12 months before and after the policy change in intervention centres and before and after a corresponding reference point in control centres. The reference point in control centres was defined as the mean discontinuation date across intervention centres RESULTS: Overall consent rates increased from 27.8% to 37.1% after the intervention or reference point (+9.3, 95% CI 3.3 to 15.4, p=0.003). In intervention centres, the consent rates rose from 27.1% to 42.9% (+15.8, 95% CI 8.6 to 23.0, p<0.001) and enrolment rates rose proportionally from 9.9% to 16.6% (+6.7, 95% CI 1.5 to 11.9, p=0.011), whereas in control centres, consent and enrolment rates remained unchanged. CONCLUSION:Restricting open-label access to an off-label investigational drug can substantially increase parental consent and patient enrolment in neonatal RCTs. To promote both ethical recruitment and optimal enrolment, future trials should explicitly discuss equipoise in each contributing unit and align local clinical practices with the trial design prior to initiation.
OBJECTIVES:To assess the effectiveness and safety of active pharmacotherapy for patent ductus arteriosus (PDA) initiated based on echocardiography-criteria versus expectant management in extremely preterm infants <29 w gestation in the first three weeks of life. STUDY DESIGN:Systematic review with meta-analysis and trial sequential analysis (TSA). We searched PubMed, Embase, CENTRAL and Emcare for randomised trials published between 2010 and May 2026. We synthesised results using random-effects meta-analysis and conducted a TSA. PATIENTS:Extremely preterm infants with PDA considered as significant on echocardiography. INTERVENTIONS:Pharmacotherapy versus expectant management. MAIN OUTCOME MEASURES:Mortality by 36 weeks postconceptional age or before discharge and chronic lung disease (CLD). RESULTS:We included 12 trials involving 2344 extremely preterm infants. Meta-analysis found increased risk of mortality with active pharmacotherapy (RR 1.34, 95% CI 1.08 to 1.67; p=0.008, I2=0%; 12 randomised controlled trials (RCTs)). Number-needed-to-treat for an additional harmful outcome (i.e. mortality) was 25 (95% CI 17 to 100). On TSA conducted with the stringent alpha error 3.3% and beta 10%, the cumulative Z-score touched the O'Brien-Fleming monitoring boundary at the current sample size, supporting the meta-analysis findings under the specified TSA assumptions.For CLD, meta-analysis showed little or no difference (RR 0.99, 95% CI 0.92 to 1.06, p=0.74, I2=14%, 12 RCTs). The certainty of evidence was high for mortality and moderate for CLD. CONCLUSIONS:In extremely preterm infants, active pharmacotherapy for PDA based on current echocardiographic criteria in the first three weeks of life was associated with increased mortality with a clinically important number needed to harm. These findings should inform treatment decisions and discussions with parents while ongoing research seeks to identify infants who may benefit from treatment. PROSPERO REGISTRATION NUMBER:CRD420261303992.
OBJECTIVE:To investigate the impact of transition from National Institute for Health and Care Excellence (NICE) guidelines to Kaiser Permanente Neonatal Sepsis Risk Calculator (KP-SRC) on early-onset sepsis (EOS) diagnosis and mortality. STUDY DESIGN:Pre-post intervention analysis across 16 NHS hospital Trusts in England (2015-2023) 18 months before and after NICE to KP-SRC transition. Liveborn infants of any gestational age (N=222 122) were extracted from Hospital Episode Statistics and linked to national microbiological data and birth and death registrations. MAIN OUTCOMES:Cases were identified within first 3 days of life during birth admission or first 7 days if readmitted and defined microbiologically (positive microbiology from normally sterile site) or clinically (International Classification of Diseases, 10th Revision codes). Deaths occurring within the neonatal period attributable to EOS and proportion of EOS cases diagnosed during readmission were identified. RESULTS:There was no evidence of an increase in late diagnosis of EOS after KP-SRC implementation across hospitals combined, with the proportion of microbiologically confirmed cases diagnosed on readmission similar to pre-implementation (9.6% vs 10.8%; p=0.67). Variation between hospitals was observed, with non-significant increases in readmission diagnosis (vs diagnosis in birth episode) post implementation in 9 of 15. There was no difference in mortality for microbiologically confirmed cases or deaths based on clinical diagnosis though the study was not powered for these outcomes. CONCLUSION:No overall increase in late diagnoses due to EOS was observed after switching to KP-SRC but variation between hospitals, including non-significant increases in readmission diagnoses in some, injects caution and underscores the importance of local monitoring post implementation.
Postnatally acquired cytomegalovirus infection (pCMV) in very preterm and/or very low-birth-weight infants (GA<32w/VLBW) is increasingly recognised as a cause of acute and longer-term morbidity. This review presents a narrative synthesis of evidence published between April 2019 and October 2025, with expert commentary on diagnosis and management. Across study designs, there is growing evidence linking pCMV to prolonged hospitalisation, respiratory, gastrointestinal and ophthalmic morbidity. Prospective surveillance data reveal pCMV as a frequently underdiagnosed cause of sepsis-like presentations, cardiorespiratory instability and necrotising enterocolitis, often occurring without typical signs such as thrombocytopenia or liver derangement. A lower threshold for early CMV testing in symptomatic infants may identify candidates for timely targeted treatment and support antibiotic stewardship. Emerging evidence suggests that viral dynamics in pCMV differ substantially from congenital CMV (cCMV) because viral shedding in urine and saliva can be delayed or intermittent in acute disease, blood PCR may be the most pragmatic diagnostic modality for early symptomatic presentations. Targeted CMV screening of all GA<32w/VLBW infants at birth helps distinguish pCMV from cCMV, which is essential for management. Antiviral treatment with ganciclovir or valganciclovir is considered in infants with severe or sustained end-organ disease. Therapy is informed by clinical response, blood viral load, emerging pharmacokinetic data and therapeutic drug monitoring to balance efficacy with haematological toxicity. Larger-scale collaborative research is needed to ascertain the burden of pCMV disease and support future randomised controlled trials evaluating prevention and treatment strategies.
OBJECTIVE:The optimal positive end-expiratory pressure (PEEP) to aerate the preterm lung directly after birth is still unknown. We aimed to determine whether a PEEP of 10 vs 6 cmH2O in the first 10 min after birth influences short and long-term outcomes. METHODS:This retrospective preimplementation and postimplementation study analysed preterm infants with a gestational age (GA) <32 weeks born between 2015 and 2023 at the University Hospital Tübingen. The local protocol regarding initial PEEP level was changed in 2019, resulting in a high-PEEP (10 cmH2O) versus a low-PEEP (6 cmH2O) group. RESULTS:718 infants with median GA of 29 weeks were included. There was no group difference in the primary outcome, that is, the SpO2/FiO2 ratio at 5 min after birth. More infants exposed to low PEEP received less-invasive surfactant administration (151 (41%) vs 101 (29%), p<0.05) and had a longer duration of non-invasive ventilation (30 (8-46) vs 19 (6-43.5) days, p<0.05). Moreover, they had a higher risk of being intubated within 72 hours of birth (OR 1.7; 95% CI 1.07 to 2.66, p<0.05) and of developing bronchopulmonary dysplasia (OR 1.7; 95% CI 1.14 to 2.64, p<0.05) or retinopathy of prematurity (OR 1.8; 95% CI 1.17 to 2.79, p<0.05). CONCLUSION:Applying a higher PEEP (10 cmH2O) postnatally might be beneficial in preventing short as well as long-term outcomes in preterm infants, but randomised controlled trials are needed to confirm this hypothesis.
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 <34 weeks' gestation between 2008 and 2019 admitted to a National Health Service neonatal unit in England (n=165 269). 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.
OBJECTIVE:Hypoglycaemia is common in neonates. Repeated hypoglycaemic episodes impose a risk of subsequent neurodevelopmental impairment. We aimed to assess the feasibility of using continuous glucose monitoring (CGM) in a group of infants at risk of hypoglycaemia. DESIGN:Observational feasibility study. SETTINGS:Level 2 neonatal unit, Norway. PATIENTS:Infants of mothers with diabetes or infants born large for gestational age. INTERVENTIONS:A blinded CGM-device was applied on the upper lateral thigh of the neonate shortly after birth to record tissue glucose during the infant's admission at the postnatal ward. Capillary blood glucose screening samples were analysed by oxidase method. MAIN OUTCOMES:Accuracy of tissue glucose values. Tissue glucose variations during the first 3 days after birth. Number of silent hypoglycaemic events. RESULTS:We included 25 infants. Tissue glucose values were higher than blood glucose values but estimated discrepancy decreased from 1.0 mmol/L at 6 hours to 0.5 mmol/L at 18 hours of age. The lowest tissue glucose values were observed around 50 hours postnatal age. From 28 hours postnatal age until discharge, CGM detected 49 silent hypoglycaemic events in 10 infants. We observed no significant harm from the devices on skin or subcutaneous tissue. CONCLUSION:Accuracy of tissue glucose increased with time in comparison to capillary blood glucose, but the device could not detect glucose values <2.2 mmol/L. Tissue glucose levels were lowest at ~50 hours postnatal age and hypoglycaemia occurred later than expected. CGM may be a feasible supplement, but approved CGM-devices for neonates are called for.
