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Background and Objective: The effects of neonatal hypoglycemia on the developing brain are well known, resulting in poor neurological outcomes. We aimed to perform an updated meta-analysis on neonatal hypoglycemia, the severity of hypoglycemia, and the associated neurodevelopmental outcomes from infancy to adulthood., Methods: A systematic literature search was conducted from inception until March 2024, using the PubMed, CINAHL, Embase, and the CENTRAL databases. Randomized/quasi-randomized trials and observational studies that evaluated at least one of the pre-specified outcomes were included. A random-effects model meta-analysis was performed to yield the pooled OR and its 95% CI for each outcome due to the expected heterogeneity in the studies. The study findings were reported as per the PRISMA guidelines. Neurodevelopmental impairment (NDI), cognitive impairment, and visual-motor or visual impairment were the primary outcomes., Results: A total of 17 studies (19 publications) were included in the final analysis. NDI, as defined by authors, was significantly higher in early- (OR = 1.16; 95% CI = 1.11-1.43) and mid-childhood (OR = 3.67; 95%CI = 1.07-12.2) in infants with neonatal hypoglycemia. 'Any cognitive impairment' was significantly more common in infants with neonatal hypoglycemia (OR = 2.12; 95%CI = 1.79-2.52). Visual-motor impairment (OR = 3.33; 95%CI = 1.14-9.72) and executive dysfunction (OR = 1.99; 95%CI = 1.36-2.91) were also more common in the hypoglycemic group. No difference in the incidence of epilepsy, motor impairment, emotional-behavioral problems, or hearing impairment were noted. Certainty of evidence was adjudged as 'low' to 'very low' for most outcomes. The severity of hypoglycemia was studied at different intervals, with NDI more common with a blood glucose interval between 20 and 34 mg/dL (1.1-1.9 mmol/L)., Conclusions: Low-quality evidence from large observational studies finds a significant association with hypoglycemia in the early neonatal period and long-term neurodevelopmental problems. Additional studies with long enough follow-up are paramount to determine the cut-off concentration and to quantify the impact beyond the infancy period.

This meta-analysis assessed short-term outcomes after using human milk-derived fortifiers (HMFs) compared with bovine milk fortifiers (BMFs) in preterm infants fed an exclusive human milk (HM) diet, either mother's own milk (MOM) or donor human milk (DHM). We searched PubMed, Embase, Google Scholar, CENTRAL and CINHAL between January 2015 and August 2023 for studies reporting outcomes in infants with ≤28 weeks gestation and/or birthweight ≤ 1500 g on an exclusive human milk diet fortified with HMF versus BMF. The primary outcomes were death and NEC (stage ≥ 2). Four studies with a total of 681 infants were included. Mortality was significantly lower in infants fed with an HM-HMFs diet (four studies, 681 infants; RR = 0.50, 95% CI = 0.26-0.94; p = 0.03; I 2 = 0%), NEC was similar between the two groups (four studies, 681 infants; RR = 0.48, 95% CI = 0.20-1.17; p = 0.11; I 2 = 39%). BPD was higher in the HM-BMFs group (four studies, 663 infants; RR = 0.83, 95% CI = 0.69-1.000; p = 0.05, I 2 = 0%), although not statistically significant. No differences were found for sepsis (RR = 0.97, 95% CI = 0.66-1.42; p = 0.96; I 2 = 26%) or combined ROP (four studies, 671 infants; RR = 0.64, 95% CI = 0.53-1.07; p = 0.28; I 2 = 69%). An HM-HMFs diet could possibly be associated with decreased mortality with no association with NEC, BPD, sepsis, or ROP. This meta-analysis was limited by the small number of studies included. However, the results should not be refuted for this reason as they provide an impetus for subsequent clinical trials to assess the observed associations.

Background: Retinopathy of prematurity (ROP) and abnormal brain development share similar risk factors and mechanisms. There has been contrasting evidence on the association of ROP with adverse neurodevelopmental outcomes., Objective: We analysed the association between ROP at levels of severity and treatment with all neurodevelopmental outcomes until adolescence., Data Source: We followed PRISMA guidelines and searched Medline and Embase between 1 August 1990 and 31 March 2022., Study Selection and Participants: Randomised or quasi-randomised clinical trials and observational studies on preterm infants (<37 weeks) with ROP [type 1 or severe ROP, type 2 or milder ROP, laser or anti-vascular endothelial growth factor (VEGF) treated] were included., Data Extraction and Synthesis: We included studies on ROP and any neurocognitive or neuropsychiatric outcomes., Outcomes: The primary outcomes were as follows: cognitive composite scores evaluated between the ages of 18 and 48 months by the Bayley Scales of Infant and Toddler Development (BSID) or equivalent; neurodevelopmental impairment (NDI; moderate to severe NDI or severe NDI), cerebral palsy, cognitive impairment; and neuropsychiatric or behavioural problems. The secondary outcomes were as follows: motor and language composite scores evaluated between the ages of 18 and 48 months by BSID or equivalent; motor/language impairment; and moderate/severe NDI as defined by the authors., Results: In preterm infants, "any ROP" was associated with an increased risk of cognitive impairment or intellectual disability [ n  = 83,506; odds ratio (OR): 2.56; 95% CI: 1.40-4.69; p  = 0.002], cerebral palsy ( n  = 3,706; OR: 2.26; 95% CI: 1.72-2.96; p  < 0.001), behavioural problems ( n  = 81,439; OR: 2.45; 95% CI: 1.03-5.83; p  = 0.04), or NDI as defined by authors ( n  = 1,930; OR: 3.83; 95% CI: 1.61-9.12; p  = 0.002). Type 1 or severe ROP increased the risk of cerebral palsy (OR: 2.19; 95% CI: 1.23-3.88; p  = 0.07), cognitive impairment or intellectual disability ( n  = 5,167; OR: 3.56; 95% CI: 2.6-4.86; p  < 0.001), and behavioural problems ( n  = 5,500; OR: 2.76; 95% CI: 2.11-3.60; p  < 0.001) more than type 2 ROP at 18-24 months. Infants treated with anti-VEGF had higher odds of moderate cognitive impairment than the laser surgery group if adjusted data (gestational age, sex severe intraventricular haemorrhage, bronchopulmonary dysplasia, sepsis, surgical necrotising enterocolitis, and maternal education) were analysed [adjusted OR (aOR): 1.93; 95% CI: 1.23-3.03; p  = 0.04], but not for cerebral palsy (aOR: 1.29; 95% CI: 0.65-2.56; p  = 0.45). All outcomes were adjudged with a "very low" certainty of evidence., Conclusion and Relevance: Infants with "any ROP" had higher risks of cognitive impairment or intellectual disability, cerebral palsy, and behavioural problems. Anti-VEGF treatment increased the risk of moderate cognitive impairment. These results support the association of ROP and anti-VEGF treatment with adverse neurodevelopmental outcomes., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022326009., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Diggikar, Gurumoorthy, Trif, Mudura, Nagesh, Galis, Vinekar and Kramer.)