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Background: Pre-clinical research, which encompasses studies in animals and in the laboratory, has made significant contributions to the improvement of neonatal outcomes. Methods: Here, we describe examples of how pre-clinical research can be the starting point on the journey to the development of new interventions to improve neonatal care and outcomes and discuss recent progress in ensuring methodological and ethical rigour in pre-clinical research involving animal models. Results: Studies in pregnant sheep led to the serendipitous discovery that preterm lambs born after exogenous corticosteroid exposure were able to aerate their lungs. Subsequent clinical trials confirmed that antenatal corticosteroids given to women at risk of preterm delivery substantially reduce mortality and morbidity in babies born preterm. Animal research also contributed to discoveries in the mechanism of brain injury after hypoxic ischaemic encephalopathy, leading to the use of therapeutic hypothermia as an effective treatment. However, animals are sentient creatures and there are significant ethical concerns with their use in studies to benefit human health. Mandated institutional animal research ethics committees ensure adherence to ethical requirements. To provide high-quality data which can be translated into clinical research, pre-clinical research needs to follow rigorous standards of study design and reporting. The ARRIVE guidelines provide guidance for pre-clinical research similar to that provided in the CONSORT guidelines for clinical trials and are gaining acceptance among researchers and journal editors. Conclusion: Improved scientific rigour in the use of animal research will increase the likelihood that pre-clinical research will continue to translate into improved neonatal outcomes. [ABSTRACT FROM AUTHOR]

Background: Milk curd obstruction (MCO), in which milk becomes inspissated, is a rare, serious, complication of preterm birth. Case reports implicate male sex and bovine-derived human milk fortifier (HMF) use as predisposing factors. We investigated this through a case-control study., Methods: MCO cases in the Starship Child Health neonatal database between 2008 and 2020 were matched with controls in a 1:2 ratio based on gestational age (±1 week), birth weight (±200 g) and date of birth (±1 month). Data were analysed using the Student's t-test, Mann-Whitney U-test or χ² test as appropriate. Data are median (IQR) or n (%)., Results: Of 20 MCO cases, gestation was 26.1 (24.5-28.1) weeks, birth weight was 822 (713-961) g, 15 (75%) were male. 40 controls were well-matched for gestation (26.1 (24.8-27.9) weeks) and birth weight (849 (690-1066) g) but only 18 (45%) were male (p=0.05). MCO occurred at 21 (15-33) days; 6 (30%) cases died compared with 3 (7.5%) controls (p=0.06). HMF was commenced at 243 (150-309) hours in cases and 224 (172-321) hours in controls (p=0.95); full-fortification (manufacturer's recommended dose) was achieved in 8 (40%) cases and 27 (68%) controls (p=0.08). In cases, MCO occurred 10 (7-17) days after commencing HMF. Medically/surgically-managed gut pathology occurred in 7 (35%) cases prior to MCO but in no controls (p<0.001)., Conclusions: Our data support male sex but not HMF use as a predisposition to MCO. Evidence of prior medical/surgical gut pathology may be a premonition for MCO; however, further research is required to confirm this., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neonatal encephalopathy (NE) is a multi-organ condition potentially leading to death or long-term neurodisability. Therapeutic hypothermia is the standard treatment for NE; however, long-term impairments remain common. Studies of new treatments for NE often measure and report different outcomes. Core outcome sets (COSs), a minimum set of outcomes to be measured and reported in all studies for a condition, address this problem. This paper aimed to identify outcomes reported (primary, secondary, adverse events and other reported outcomes) in (1) randomised trials and (2) systematic reviews of randomised trials of interventions for the treatment of NE in the process of developing a COS for interventions for the treatment of NE., Methods: We completed a systematic search for outcomes used to evaluate treatments for NE using MEDLINE, Embase, Cochrane CENTRAL, the Cochrane Database of Systematic Reviews and the WHO International Clinical Trials Registry Platform. Two reviewers screened all included articles independently. Outcomes were extracted verbatim, similar outcomes were grouped and outcome domains were developed., Results: 386 outcomes were reported in 116 papers, from 85 studies. Outcomes were categorised into 18 domains. No outcome was reported by all studies, a single study reported 11 outcomes and it was not explicitly stated that outcomes had input from parents., Discussion: Heterogeneity in reported outcomes means that synthesis of studies evaluating new treatments for NE remains difficult. A COS, that includes parental/family input, is needed to ensure consistency in measuring and reporting outcomes, and to enable comparison of randomised trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate in extremely low birthweight (ELBW; <1000 g) babies the associations between refeeding syndrome (serum phosphate <1.4 mmol·L -1 and serum total calcium>2.8 mmol·L -1 ) and hypophosphataemia in the first week and death or neurodisability at 2 years' corrected age (CA)., Design: Secondary cohort analysis of the ProVIDe trial participants with serum biochemistry within 7 days of birth. At 2 years' CA, neurodisability was assessed by Bayley Scales of Infant Development Edition III and neurological examination. Associations between neurodisability and other variables were analysed using t-tests and logistic regression adjusted for sex and smallness-for-gestational age., Setting: Six tertiary neonatal intensive care units (NICUs) in New Zealand., Participants: 352 ELBW babies born between 29 April 2014 and 30 October 2018., Main Outcome Measure: Death or neurodisability at 2 years' CA., Results: Fifty-nine babies died, two after discharge from the NICU. Of the 336 babies who survived to 2 years' CA, 277 had neurodevelopmental assessment and 107 (39%) had a neurodisability. Death or neurodisability was more likely in babies who had refeeding syndrome (aOR 1.96 (95% CI 1.09 to 3.53), p=0.02) and in babies who had hypophosphataemia (aOR 1.74 (95% CI 1.09 to 2.79), p=0.02). Hypophosphataemia was associated with increased risk of death (aOR 2.07 (95% CI 1.09 to 3.95), p=0.03)) and severe hypophosphataemia (<0.9 mmol·L -1 ) with increased risk of death (aOR 2.67 (95% CI 1.41 to 5.00), p=0.002) and neurodisability (aOR 2.31 (95% CI 1.22 to 4.35), p=0.01)., Conclusions: In ELBW babies, refeeding syndrome and hypophosphataemia in the first week are associated with death or neurodisability. Until optimal phosphate requirements are determined through further research, monitoring for hypophosphataemia and mitigation strategies are indicated., Trial Registration Number: ACTRN12612001084875., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Fetal growth restriction (FGR) is associated with compromised growth and metabolic function throughout life. Intrauterine therapy of FGR with intra-amniotic insulin-like growth factor-1 (IGF1) enhances fetal growth and alters perinatal metabolism and growth in a sex-specific manner, but the adult effects are unknown. We investigated the effects of intra-amniotic IGF1 treatment of FGR on adult growth and body composition, adrenergic sensitivity, and glucose-insulin axis regulation. Placental embolization-induced FGR was treated with four weekly doses of 360 µg intra-amniotic IGF1 (FGRI) or saline (FGRS). Offspring were raised to adulthood (18 mo: FGRI, n = 12 females, 12 males; FGRS, n = 13 females, 10 males) alongside offspring from unembolized and untreated sheep (CON; n = 12 females, 21 males). FGRI females had increased relative lean mass compared with CON but not FGRS ( P < 0.05; 70.6 ± 8.2% vs. 61.4 ± 8.2% vs. 67.6 ± 8.2%), decreased abdominal adipose compared with CON and FGRS ( P < 0.05; 43.7 ± 1.2% vs. 49.3 ± 0.9% vs. 48.5 ± 1.0%), increased glucose utilization compared with FGRS but not CON ( P < 0.05; 9.6 ± 1.0 vs. 6.0 ± 0.9 vs. 7.6 ± 0.9 mg·kg -1 ·min -1 ), and increased β-hydroxybutyric acid:nonesterified fatty acid ratio in response to adrenaline compared with CON and FGRS ( P < 0.05; 3.9 ± 1.4 vs. 1.1 ± 1.4 vs. 1.8 ± 1.4). FGRS males were smaller and lighter compared with CON but not FGRI ( P < 0.05; 86.8 ± 6.3 vs. 93.5 ± 6.1 vs. 90.7 ± 6.3 kg), with increased peak glucose concentration (10%) in response to a glucose load but few other differences. These effects of intra-amniotic IGF1 therapy on adult body composition, glucose-insulin axis function, and adrenergic sensitivity could indicate improved metabolic regulation during young adulthood in female FGR sheep.