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Sepsis due to the administered probiotic strain/s is a barrier against adoption of prophylactic probiotic supplementation in preterm infants to reduce the risk of necrotising enterocolitis (NEC ≥ Stage II), all-cause mortality, late-onset sepsis, and feeding intolerance. We aimed to conduct a systematic review for reports of probiotic sepsis in preterm infants (gestation < 37 weeks). Databases including PubMed, Embase, Emcare, Cochrane Central library, and Google Scholar were searched in August 2021 and updated in Jan 2022. Probiotic sepsis was defined as positive blood/CSF culture isolating administered probiotic strain with symptoms suggestive of infection. Data collection included birth weight, gestation, comorbidities (e.g. gut surgery, NEC), presence of central venous catheters, treatment, and outcome. Literature search revealed 1569 studies. A total of 16 reports [randomised control trial (RCT): none; non-RCT: 1; case series: 8; case report: 7] involving 32 preterm infants with probiotic sepsis were included after exclusions for various reasons. Majority of the cases were born < 32 weeks’ gestation. Bifidobacterium ( N  = 19) was the most commonly isolated organism followed by Lactobacillus ( N  = 10), and Saccharomyces ( N  = 3). A total of 25/32 cases were confirmed to be due to the administered probiotic strain on full genomic analysis. Two studies reported one neonatal death each. Twelve neonates had comorbidities. Majority were treated with antibiotics (29/32) whereas others (3/32) required antifungal treatment. Conclusion : Probiotics sepsis is relatively an uncommon event in preterm infants. Majority of the cases recovered after antibiotic or antifungal treatment. The importance of optimal surveillance and treatment of probiotic sepsis and research towards alternatives to probiotics (e.g. postbiotics) is emphasised. What is Known: • Probiotics have been shown to reduce necrotising enterocolitis, late-onset sepsis, all-cause mortality, and time to reach full enteral feeds in preterm infants. • Despite the evidence, use of probiotics is not universal due to concerns regarding probiotic-associated sepsis in preterm infants. What is New: • This comprehensive systematic review showed that probiotic sepsis is a relatively rare phenomenon in preterm infants. • All except one case where the diagnosis was uncertain recovered after antimicrobial therapy.

Birthing in a hospital with on-site surgical facilities (co-located care) is considered preferable for neonates with surgical conditions. However, it may not always be feasible. Whether transfer of surgical neonates from birth hospital to a surgical facility affects the outcomes of this cohort is unclear. We conducted a systematic review to investigate the association of birth location/transfer with all-cause mortality and disability among neonates with congenital/acquired surgical conditions. Data Sources from PubMed, Embase, CINAHL, and Web of Science were searched till December 2024. Studies from high-income countries (HICs) comparing infants transferred to a surgical center for surgery versus infants born and operated in a co-located care facility were included. Random effects model was used for meta-analysis. The quality of studies and certainty of evidence were assessed using Newcastle-Ottawa Scale and the GRADE framework respectively. The primary outcomes of interest were all-cause mortality and neurodevelopmental impairment at latest follow up. A total of 61 studies from 20 HICs were included. Compared to co-located care, transfer for surgery did not increase the odds of risk-adjusted and crude mortality in neonates with congenital diaphragmatic hernia [adjusted odds ratio (aOR):0.86 (0.49 to 1.49), 5 studies, 8366 infants; crude OR:0.68 (0.51 to 0.91, i.e., decreased mortality), 22 studies, 12970 infants], critical congenital heart disease [aOR:0.79 (0.42 to 1.48), 3 studies, 13485 infants; OR:1.04 (0.66 to 1.64), 10 studies, 14447 infants], surgical necrotizing enterocolitis [aOR:0.99 (0.61 to 1.61), 4 studies, 5891 infants; OR:1.03 (0.64 to 1.65), 5 studies, 5915 infants], gastroschisis [aOR:1.07 (0.68 to 1.68), 2 studies, 5294 infants; OR:0.80 (0.48 to 1.35), 11 studies, 8708 infants], tracheo-oesophageal fistula [aOR:0.97 (0.39 to 2.39), 1 study, 937 infants; OR:0.62 (0.37 to 1.04), 4 studies, 4050 infants], congenital or perinatal intestinal conditions [OR:2.69 (0.26 to 28.34), 4 studies, 1799 infants]. Neurodevelopmental outcomes between the groups were comparable in the three studies that reported this outcome. Whilst many included studies were of good quality, certainty of evidence was very low due to their observational design and heterogeneity. In conclusion, transfer of neonates from the birth hospital to another facility for surgical intervention was not associated with increased risk of mortality or disability. The evidence from this comprehensive meta-analysis would be useful for clinicians, parents and health policy makers. Systematic review registration: PROSPERO CRD 42024565651.

Previous systematic reviews suggest reduction in necrotizing enterocolitis (NEC) among preterm infants supplemented with erythropoietin (EPO). We aimed to update our 2018 systematic review in this field considering the evidence accumulated over the last 3 years. Randomized controlled trials (RCTs) reporting the effect of early EPO supplementation vs placebo/no EPO supplementation on any stage NEC in preterm infants were included. Fixed effect model was used for meta-analysis. Trial sequential analysis (TSA) was conducted to verify the effects of EPO on NEC after accounting for repeated significance testing. A total of 22 RCTs ( n  = 5359) were included, of which six were new ( n  = 2541 additional preterm infants) in comparison to our previous systematic review. EPO significantly decreased the risk of any stage NEC (232/2669 (8.7%) vs 313/2690 (11.6%); RR: 0·76; TSA adjusted 95% CI (0·64, 0·90); p  = 0·0008, number needed to treat (NNT) = 34). The risk of definite NEC (≥ Stage II) was also significantly reduced by EPO administration (105/2219 (4.7%) vs 141/2246 (6.3%); RR: 0.77; 95% CI (0.61, 0.98); p  = 0.03, NNT: 62). However, the results for definite NEC were no longer significant on sensitivity analyses that included (a) only double-blind RCTs and (b) only prospectively registered trials. The quality of evidence was deemed moderate-to-low for the reported outcomes. Conclusion : There is moderate to low-quality evidence that early prophylactic EPO reduces any stage and ≥ Stage II NEC in preterm neonates. Prospectively registered, adequately powered, double-blind RCTs are required to confirm these findings. What is Known: • Experimental studies have shown that erythropoietin (EPO) has gastrointestinal trophic effects. • Systematic reviews have shown that early treatment with EPO may decrease the risk of gut injury in preterm or low birth weight infants. What is New: • Early EPO supplementation significantly reduced the incidence of any stage NEC and definite NEC in preterm infants < 34 weeks of gestation. • EPO had no significant effect on definite NEC in the analyses that included only double-blinded and prospectively registered RCTs. How might it impact clinical practice in the foreseeable future? • Early prophylactic EPO can be recommended for NEC prevention if its benefits are consistently demonstrated in adequately powered randomized trials with a low risk of bias.

The majority of extremely low birth weight (ELBW) neonates receive red blood cell (RBC) transfusions; at least 50% receive multiple transfusions. Anemia care bundles could be the most effective approach to reduce transfusion rates. We conducted a quality improvement non-controlled before-and-after retrospective study involving 345 ELBW infants admitted over a 5-year period in two consecutive epochs before and after implementation of an anemia care bundle in January 2017. Bundle components included (a) prophylactic subcutaneous erythropoietin twice each week (600 IU/kg/week) from day 7 through 8 weeks of age and (b) blood sampling stewardship in the first five postnatal weeks. Early postnatal blood sampling losses were significantly reduced following the implementation of the care bundle (21.2 ml/kg vs 25 ml/kg, P < 0.001). We found a 50% reduction in the rate of multiple RBC transfusions (adjusted RR 0.45, 95% CI: 0.34–0.59) and a reduced odds of necrotizing enterocolitis (NEC) (4% vs 10%, adjusted OR 0.38 (95% CI: 0.15–0.78)) among infants that received the anemia care bundle (n = 182 infants). The overall transfusion rate, number and volume of transfusions, and multiple donor exposures were also significantly reduced.Conclusion: The combination of extended subcutaneous erythropoietin administration and reduced early postnatal blood sampling was associated with a significant reduction in the rate of multiple erythrocyte transfusions and NEC in ELBW neonates.What is known:• The majority of extremely low birth weight neonates continue to require blood transfusions despite advances in standardized transfusion practices; at least 50% require multiple transfusions.• Anemia care bundles, employing a combination of anemia prevention strategies, can effectively reduce the RBC transfusion rates in ELBW infants.What is new:• A combination of extended subcutaneous erythropoietin supplementation and blood sampling stewardship practices reduced the rate of multiple RBC transfusions in ELBW neonates by 50%.• Implementation of the anemia care bundle was associated with a significant reduction in the rates of necrotizing enterocolitis.

ObjectiveTo evaluate the effect of minimising blood sampling losses on red blood cell (RBC) transfusion-related outcomes in preterm infants <37 weeks’ gestation.Study designWe searched PubMed, Embase, Web of Science and Google Scholar from inception to October 2024 for studies that evaluated sampling stewardship practices (SSP) in preterm infants during initial hospitalisation. Two authors independently screened articles that evaluated one or more sampling approaches to minimise blood loss or non-invasive methods to avoid sampling losses. Meta-analysis was conducted using a random effects model.ResultsEighteen studies (4 randomised controlled trials (RCTs) and 14 non-randomised studies) were included. Five studies used umbilical cord blood sampling, four used protocol-based sampling and two used retransfusion of sampled blood back to the infant as an SSP. Sampling care bundles were used in seven studies. Meta-analysis showed that SSP reduced early RBC transfusion rates (RCTs: Relative risk(RR) =0.50, 95% CI 0.36, 0.68; non-RCTs: RR=0.78, 95% CI 0.69, 0.90), the average number of transfusions per infant (RCTs: mean difference=−0.4 transfusions, 95% CI −0.68, –0.05; non-RCTs: standardised mean difference=−0.40, 95% CI −0.55, –0.25) and the rates of multiple transfusions (non-RCTs: RR=0.51, 95% CI 0.42, 0.62). There were no significant effects on mortality and other morbidities. Certainty of evidence was high for transfusion-related outcomes and moderate for other outcomes.ConclusionSSPs are associated with a significant reduction in RBC transfusion rates among very and extremely preterm infants. Large RCTs are required to assess the effects of SSP on other important outcomes.PROSPERO registration numberCRD42024539665.

ObjectiveTo study the efficacy of intranasal fentanyl as an adjunct for pain management during screening for retinopathy of prematurity (ROP) in preterm infants.Study designIn this single center, double blinded, randomized controlled trial, preterm neonates between 30 and 34 weeks postmenstrual age received either intranasal fentanyl (2 mcg/kg) or intranasal normal saline through a mucosal atomization device 5 min prior to the first ROP-screening examination. Both the groups received standard pain relief strategies (oral sucrose, 0.5% proparacaine eye drops and physical containment). The primary outcome was premature infant pain profile-revised (PIPP-R) score during the screening.ResultsA total of 111 infants were enrolled. PIPP-R score during the retinal examination was significantly lower in the fentanyl group (8.3 versus 11.5, mean difference: 3.2 (2.46–4.06), P < 0.001). There was no significant difference in the incidence of adverse effects.ConclusionIntranasal fentanyl significantly reduced the pain associated with retinal examination without increasing the risk of respiratory depression. Large RCTs are required to verify the efficacy and safety of intranasal fentanyl for acute procedural pain in neonates.Clinical Trial RegistrationCTRI/2017/12/011016.

AimTo determine predictors of rescue treatment among infants treated for retinopathy of prematurity and to evaluate their ocular outcomes at 18–24 months of corrected age.MethodsThis is a single centre retrospective study of infants who received treatment for type 1 ROP, using laser photocoagulation or anti VEGF agents. Multivariable logistic regression was used to generate a prediction model for rescue treatment of ROP. The primary outcome was an abnormal refractive outcome by 24 months of corrected age, among infants primarily treated with laser therapy.ResultsTwo hundred and eight infants (including 416 eyes) who received single (n = 151) or rescue (multiple) treatments (n = 57) were included. Ninety three percent of the infants were primarily treated with laser photocoagulation. Lower gestational age, small for gestational age, early packed red blood cell transfusion (within 2 weeks of postnatal age), and presence of Zone 1 retinopathy predicted the need for rescue treatment in treated infants [area under the receiver operating characteristic curve: 0.81 (0.73–0.89)]. The incidence of abnormal refractive outcome, assessed in a total of 174 infants, was found to be significantly higher in the rescue treatment group (67% versus 21%, adjusted odds ratio: 7.56 (3.3–17.2), P < 0.001). Myopia, very high myopia and use of spectacles was significantly higher in the rescue treatment group (P < 0.001 for each).ConclusionsRescue treatment for ROP was associated with an increased incidence of refractive errors and requirement of spectacles by 2 years of age. Larger prospective multicentre studies are required to confirm the findings from our study.

Since the coronavirus disease (COVID-19) pandemic hit the globe in early 2020, we have steadily gained insight into its pathogenesis; thereby improving surveillance and preventive measures. In contrast to other respiratory viruses, neonates and young children infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have a milder clinical presentation, with only a small proportion needing hospitalization and intensive care support. With the emergence of novel variants and improved testing services, there has been a higher incidence of COVID-19 disease reported among children and neonates. Despite this, the proportion of young children with severe disease has not increased. Key mechanisms that protect young children from severe COVID-19 disease include the placental barrier, differential expression of angiotensin-converting enzyme 2 (ACE-2) receptors, immature immune response, and passive transfer of antibodies via placenta and human milk. Implementing mass vaccination programs has been a major milestone in reducing the global disease burden. However, considering the lower risk of severe COVID-19 illness in young children and the limited evidence about long-term vaccine safety, the risk–benefit balance in children under five years of age is more complex. In this review, we do not support or undermine vaccination of young children but outline current evidence and guidelines, and highlight controversies, knowledge gaps, and ethical issues related to COVID-19 vaccination in young children. Regulatory bodies should consider the individual and community benefits of vaccinating younger children in their local epidemiological setting while planning regional immunization policies.

BackgroundParent/caregiver-completed developmental testing (PCDT) is integral to developmental care in children; however, there is limited information on its accuracy. In this systematic review, we compared the diagnostic accuracy of PCDT with concurrently administered Bayley Scales of Infant Development for detection of developmental delay (DD) in children below 4 years of age.MethodsWe searched databases PubMed, Embase, CINAHL, PsycINFO and Google Scholar until November 2023. Bivariate and multiple thresholds summary receiver operating characteristics were used to obtain the summary sensitivity and specificity with 95% CIs. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used for risk of bias assessment.ResultsA total of 38 studies (31 in the meta-analysis) were included. Ages and Stages Questionnaire (ASQ) and Parent Report of Children’s Abilities-Revised (PARCA-R) were the most commonly evaluated PCDTs. ASQ score >2 SD below the mean had an overall sensitivity of 0.72 (0.6, 0.82) and 0.63 (0.50, 0.75) at a median specificity of 0.89 (0.82, 0.94) and 0.81 (0.76, 0.86) for diagnosing moderate to severe DD and severe DD, respectively. PARCA- R had an overall sensitivity of 0.69 (0.51, 0.83) at median specificity of 0.75 (0.64, 0.83) for predicting severe DD. Participant selection bias and partial verification bias were found in over 50% of the studies. The certainty of evidence was low for the studied outcomes.ConclusionsThe most commonly studied parental tools, ASQ and PARCA-R, have moderate to low sensitivity and moderate specificity for detecting DD in young children. High risk of bias and heterogeneity in the available data can potentially impact the interpretation of our results.PROSPERO registration numberCRD42021268629.

Lactobacillus rhamnosus GG (LGG) is a widely used and extensively researched probiotic. Probiotic effects are considered to be strain specific. We aimed to comprehensively assess the strain-specific effects of LGG in preterm infants. A systematic review of RCTs and non-RCTs to evaluate the effect of LGG in preterm infants. We followed the Cochrane methodology, and preferred reporting items for systematic reviews (PRISMA) statement for conducting and reporting this review. We searched the Cochrane central register of controlled trials, PubMed, EMBASE and CINAHL databases till December 2023. The review was registered in PROSPERO 2022 CRD42022324933. Meta-analysis of data from RCTs that used LGG as the sole probiotic showed significantly lower risk of NEC ≥Stage II [5 RCTs, n = 851, RR:0.50 (95% CI: 0.26, 0.93), P = 0.03] in the LGG group. There was no significant difference in the risk of LOS [7 RCTs, n = 1037, RR:1.08 (95% CI 0.84, 1.39), P = 0.55], mortality [3 RCTs, n = 207, RR: 0.99 (95% CI: 0.42, 2.33), P = 0.99], time to reach full feeds [2 RCTs, n = 19, SMD = 0.11 days (95% CI: −0.22, 0.45), P = 0.51] and duration of hospital stay [3 RCTs, n = 293, SMD: −0.14 days (95% CI: −0.37 to 0.09), P = 0.23]. Meta-analysis of data from non-RCTs showed no significant effect of LGG on NEC, LOS, and mortality. RCTs showed beneficial effects of LGG when used as the sole probiotic in reducing the risk of NEC, whereas observational studies did not. Strain-specific systematic review of LGG provides important data for guiding research and clinical practice.