Lactobacillus rhamnosus GG as a probiotic for preterm infants: a strain specific systematic review and meta-analysis.

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.

Comparison of parent or caregiver-completed development screening tools with Bayley Scales of Infant Development: a systematic review and meta-analysis.

BACKGROUND: Parent/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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: The 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 NUMBER: CRD42021268629.

Effect of Minimization of Early Blood Sampling Losses Among Extremely Premature Neonates: A Randomized Clinical Trial.

OBJECTIVE: To evaluate the effect of blood sampling stewardship on transfusion requirements among infants born extremely preterm. STUDY DESIGN: In this single-center, randomized controlled trial (RCT), infants born at <28 weeks of gestation and birth weight of <1000 g were randomized at 24 hours of age to two different blood sampling approaches: restricted sampling (RS) vs conventional sampling (CS). The stewardship intervention in the RS group included targeted reduction in blood sampling volume and frequency and point of care testing methods in the first 6 weeks after birth. Both groups received early recombinant erythropoietin from day three of age. Primary outcome was the rate of early red blood cell (RBC) transfusions in the first six postnatal weeks. RESULTS: A total of 102 infants (mean gestational age: 26 weeks; birth weight: 756 g) were enrolled. Fidelity to the sampling protocol was achieved in 95% of the infants. Sampling losses in the first 6 weeks were significantly lower in the RS group (16.8 ml/kg vs 23.6 ml/kg, P < .001). The RS group had a significantly lower rate of early postnatal RBC transfusions (41% vs 73%, RR: 0.56 [0.39-0.81], P = .001). The hazard of needing a transfusion during neonatal intensive care unit (NICU) stay was reduced by 55% by RS. Mortality and neonatal morbidities were similar between the two groups. CONCLUSION: Minimization of blood sampling losses by approximately one-third in the first 6 weeks after birth leads to substantial reduction in the early red blood cell transfusion rate in infants born extremely preterm and weighing <1000 g at birth. TRIAL REGISTRATION: http://www.ctri.nic.in (CTRI/2020/01/022  964).

Meta-analysis of Cerebrospinal Fluid Cell Count and Biochemistry to Diagnose Meningitis in Infants Aged < 90 Days.

OBJECTIVE: Cerebrospinal fluid (CSF) white blood cell (WBC) count, protein, and glucose (cytochemistry) are performed to aid in the diagnosis of meningitis in young infants. However, studies have reported varying diagnostic accuracies. We assessed the diagnostic accuracy of CSF cytochemistry in infants below 90 days and determined the certainty of evidence. STUDY DESIGN: We searched PubMed, Embase, Cochrane Library, Ovid, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus databases in August 2021. We included studies that evaluated the diagnostic accuracy of CSF cytochemistry compared with CSF culture, Gram stain, or polymerase chain reaction in neonates and young infants <90 days with suspected meningitis. We pooled data using the hierarchical summary receiver operator characteristic (ROC) model. RESULTS: Of the 10,720 unique records, 16 studies were eligible for meta-analysis, with a cumulative sample size of 31,695 (15 studies) for WBC, 12,936 (11 studies) for protein, and 1,120 (4 studies) for glucose. The median (Q1, Q3) specificities of WBC, protein, and glucose were 87 (82, 91), 89 (81, 94), and 91% (76, 99), respectively. The pooled sensitivities (95% confidence interval [CI]) at median specificity of WBC count, protein, and glucose were 90 (88, 92), 92 (89, 94), and 71% (54, 85), respectively. The area (95% CI) under ROC curves were 0.89 (0.87, 0.90), 0.87 (0.85, 0.88), and 0.81 (0.74, 0.88) for WBC, protein, and glucose, respectively. There was an unclear/high risk of bias and applicability concern in most studies. Overall certainty of the evidence was moderate. A bivariate model-based analysis to estimate the diagnostic accuracy at specific thresholds could not be conducted due to a paucity of data. CONCLUSION: CSF WBC and protein have good diagnostic accuracy for the diagnosis of meningitis in infants below 90 days of age. CSF glucose has good specificity but poor sensitivity. However, we could not identify enough studies to define an optimal threshold for the positivity of these tests. KEY POINTS: · Median specificity of CSF leucocyte count, protein and glucose are similar in young infants.. · At median specificity, CSF leukocyte count and protein are more sensitive than glucose.. · Owing to inadequate data, bivariate modelling to suggest optimal diagnostic thresholds is not possible..

COVID-19 Disease in Under-5 Children: Current Status and Strategies for Prevention including Vaccination.

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.

Low dose paracetamol for management of patent ductus arteriosus in very preterm infants: a randomised non-inferiority trial.

OBJECTIVE: To compare the efficacy of low dose-short course intravenous paracetamol with a conventional dose regimen for early targeted closure of patent ductus arteriosus (PDA). DESIGN: Single-centre, double-blinded, active controlled, randomised non-inferiority trial. SETTING: Level III neonatal intensive care unit in Western India. PATIENTS: Preterm infants <30 weeks of gestation requiring mechanical ventilation, or continuous positive airway pressure with FiO2 ≥0.35 and diagnosed with a haemodynamically significant PDA (hsPDA) at 18-24 hours of postnatal age. INTERVENTIONS: Low dose (10 mg/kg/dose 6 hourly for 72 hours) versus conventional dose (15 mg/kg/dose 6 hourly for 120 hours) intravenous paracetamol treatment. MAIN OUTCOME MEASURES: Comparison of the rates of ductal closure at completion of sixth postnatal day, using a prespecified non-inferiority margin of 20%. RESULTS: A total of 102 infants were enrolled. The median gestational age and birth weight of the included infants were 26.4 weeks and 830 g. At completion of the sixth postnatal day, closure of PDA was achieved in 92% of infants in the low dose group as compared with 94% of those in the standard dose group (risk difference: -1.6%, 95% CI: -11.6% to 8.5%, p=0.38). The rates of rescue therapies, adverse effects and other neonatal morbidities were comparable in both groups. CONCLUSION: In very preterm infants on significant respiratory support, low dose-short course intravenous paracetamol treatment was non-inferior to a conventional dosing regime of paracetamol for closure of hsPDA in the first week of postnatal age. Larger studies with narrow margins of non-inferiority are required to confirm our findings. TRIAL REGISTRATION NUMBER: CTRI/2017/10/010012.

Probiotic sepsis in preterm neonates-a systematic review.

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.

Early erythropoietin for preventing necrotizing enterocolitis in preterm neonates - an updated meta-analysis.

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.

Efficacy and Safety of Two Different Flow Rates of Nasal High-Flow Therapy in Preterm Neonates ≥28 Weeks of Gestation: A Randomized Controlled Trial.

OBJECTIVE: The study aimed to compare the efficacy and safety of two different nasal high-flow rates for primary respiratory support in preterm neonates STUDY DESIGN: In this single-center, double-blinded randomized controlled trial, preterm neonates ≥28 weeks of gestation with respiratory distress from birth were randomized to treatment with either increased nasal flow therapy (8-10 L/min) or standard nasal flow therapy (5-7 L/min). The primary outcome of nasal high-flow therapy failure was a composite outcome defined as the need for higher respiratory support (continuous positive airway pressure [CPAP] or mechanical ventilation) or surfactant therapy. RESULTS: A total of 212 neonates were enrolled. Nasal high-flow failure rate in the increased flow group was similar to the standard flow group (22 vs. 29%, relative risk = 0.81 [95% confidence interval: 0.57-1.15]). However, nasal flow rate escalation was significantly more common in the standard flow group (64 vs. 43%, p = 0.004). None of the infants in the increased flow group developed air leak syndromes. CONCLUSION: Higher nasal flow rate (8-10 L/min) when compared with lower nasal flow rate of 5 to 7 L/min did not reduce the need for higher respiratory support (CPAP/mechanical ventilation) or surfactant therapy in moderately and late preterm neonates. However, initial flow rates of 5 L/min were not optimal for most preterm infants receiving primary nasal flow therapy. KEY POINTS: · Use of high nasal flows (8-10 L/min) did not reduce the need for higher respiratory support in moderately and late preterm infants.. · Nasal flow rate of 5 L/min was not optimal for most preterms with respiratory distress from birth.. · Careful patient selection and optimized flow settings could enhance nasal flow success in neonates..

Umbilical cord milking versus delayed cord clamping in term and late-preterm infants: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis to compare the efficacy and safety of umbilical cord milking (UCM) versus delayed cord clamping (DCC) in term and late-preterm infants. METHODS: MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Clinical trial registries, and Gray literature were searched for randomized controlled trials (RCTs) comparing UCM with DCC in term and late-preterm infants for both short-term and long-term outcomes. Intact and cut UCM were compared separately with DCC using subgroup analysis. We used fixed effect model to pool the data. Random effects model was used when there was significant heterogeneity. RESULTS: Nine studies (1632 infants) were included in the systematic review. Milking was performed on intact cord (i-UCM) in five studies (n = 829) and on cut cord (c-UCM) in four studies (n = 803). Cord milking significantly improved hemoglobin level at 48-72 h of life when compared to DCC (six studies, n = 924, mean difference 0.36 g/dL; 95% CI: 0.19-0.53). In addition, hemoglobin level at six to eight weeks of age was also significantly higher in the studies comparing i-UCM with DCC (two studies, n = 550: mean difference 0.16 g/dL; 95% CI: 0.06-0.27). There was no difference between the UCM group and DCC group for any other outcome. Only one study provided information on growth and hematological parameters at one year of age. Neurodevelopmental outcomes were not reported. None of the studies included non-vigorous infants. The grade of evidence was low to very low for all the outcomes studied. CONCLUSION: UCM is comparable to DCC in improving short-term hematological outcomes in term and late-preterm vigorous infants. Trials assessing the effect of UCM on important clinical and long-term outcomes among non-vigorous mature preterm infants are urgently required.

Effects of blood sampling stewardship and erythropoietin administration in extremely low birth weight infants-a quality improvement non-controlled before-and-after retrospective study.

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.

Predictors and ocular outcomes of rescue treatment in preterm infants with treated retinopathy of prematurity-a retrospective study.

AIM: To 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. METHODS: This 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. RESULTS: Two 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). CONCLUSIONS: Rescue 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.

Effect of T-Piece Resuscitator versus Self Inflating Bag on Arterial CO2 Levels in Preterm Neonates.

OBJECTIVE: To compare the effect of self-inflating bag (SIB) vs. T-piece resuscitator (TPR) on PaCO2 levels, when used for brief manual ventilation during administration of first dose of surfactant. METHODS: Preterm neonates were randomized to receive positive pressure ventilation with either self-inflating bag or T-piece resuscitator during administration of first dose of surfactant. Arterial blood gases were obtained at baseline and 1 h after the intervention. Primary outcome was the mean change in PaCO2 levels 1 h after the intervention. RESULTS: Eighty neonates were enrolled (40 in each group). The drop in PaCO2 at 1 h was significantly greater in the self inflating bag group as compared to the T-piece resuscitator group [8.96 ± 9.06 mmHg vs. 1.37 ± 9.06 mmHg, Mean difference = 7.58 mmHg, (95% CI: 3.78 to 11.4); P < 0.01]. The PaCO2 change was also statistically significant in the subgroup of infants that required only non-invasive ventilation. The need for second dose of surfactant was higher in the self-inflating bag group [77% vs. 55%, RR - 1.41 (95% CI: 1.02 to 1.94); P = 0.03]. CONCLUSIONS: T-piece resuscitator results in smaller reduction in PaCO2 levels compared to the self inflating bag, when used for brief manual ventilation during surfactant administration.

Human Milk-Derived Fortifiers Compared with Bovine Milk-Derived Fortifiers in Preterm Infants: A Systematic Review and Meta-Analysis.

This systematic review assessed outcomes after using human milk-derived fortifier (HMF) compared with bovine milk-derived fortifier (BMF) in preterm infants. Six randomized controlled trials (RCTs) were included. Meta-analysis using a random-effects model showed the following results: 1) lower risk of necrotizing enterocolitis (NEC; ≥Stage II) (RR: 0.38; 95% CI: 0.15, 0.95; P = 0.04, I2 = 9%; n = 334, 4 RCTs) and surgical NEC (RR: 0.13; 95% CI: 0.02, 0.67; P = 0.02, I2 = 0%; n = 209, 3 RCTs) in the HMF group; 2) no significant difference in mortality (RR: 0.40; 95% CI: 0.14, 1.15; P = 0.09, I2 = 0%; n = 334, 4 RCTs); 3) lower weight gain in the HMF group [mean difference (MD) = -1.08 g · kg-1 · d-1; 95% CI: -1.96, -0.21 g · kg-1 · d-1; P = 0.02, I2 = 0%; n = 241, 4 RCTs]; 4) no differences for length (MD = -0.11 cm/wk; 95% CI: -0.26, 0.04 cm/wk; P = 0.14, I2 = 68%) and head circumference (MD = -0.02 cm/wk; 95% CI: -0.08, 0.05 cm/wk; P = 0.59, I2 = 23%); and 5) no significant difference in late-onset sepsis (RR: 0.96; 95% CI: 0.56, 1.67; P = 0.90, I2 = 63%; n = 334, 4 RCTs). The beneficial effects of HMF for NEC were no longer significant in sensitivity analyses after excluding studies with high risk of bias. Quality of evidence as per Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis was low to very low, and hence the confidence in these results is low. In summary, fortification of milk in preterm infants with HMF compared with BMF decreased the risk of NEC but was associated with lower weight gain. Given the low quality of evidence, adequately powered and well-designed RCTs without the influence of industry are required in this field.

Umbilical cord milking in preterm infants: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of the efficacy and safety of umbilical cord milking in preterm infants. DESIGN: Randomised controlled trials comparing umbilical cord milking with delayed cord clamping/immediate cord clamping in preterm infants were identified by searching databases, clinical trial registries and reference list of relevant studies in November 2019. Fixed effects model was used to pool the data on various clinically relevant outcomes. MAIN OUTCOME MEASURES: Mortality and morbidities in preterm neonates. RESULTS: Nineteen studies (2014 preterm infants) were included. Five studies (n=922) compared cord milking with delayed cord clamping, whereas 14 studies (n=1092) compared milking with immediate cord clamping. Cord milking, as opposed to delayed cord clamping, significantly increased the risk of intraventricular haemorrhage (grade III or more) (risk ratio (RR): 1.95 (95% CI 1.01 to 3.76), p=0.05). When compared with immediate cord clamping, cord milking reduced the need for packed RBC transfusions (RR:0.56 (95% CI 0.43 to 0.73), p<0.001). There was limited information on long-term neurodevelopmental outcomes. The grade of evidence was moderate or low for the various outcomes analysed. CONCLUSION: Umbilical cord milking, when compared with delayed cord clamping, significantly increased the risk of severe intraventricular haemorrhage in preterm infants, especially at lower gestational ages. Cord milking, when compared with immediate cord clamping, reduced the need for packed RBC transfusions but did not improve clinical outcomes. Hence, cord milking cannot be considered as placental transfusion strategy in preterm infants based on the currently available evidence.

Probiotics for Preterm Infants in India - Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The objective of the present study is to review current evidence from randomized controlled trials (RCTs) of probiotics for preterm infants in India. A systematic review of RCTs of probiotics for preterm infants in India was conducted using Cochrane methodology and PRISMA guidelines. Fixed effects model was used for meta-analysis. Nine RCTs (n = 1514) were included. Meta-analysis showed reduced risk of necrotizing enterocolitis (NEC) ≥ Stage II {Risk ratio (RR): 0.36 [95% confidence interval (CI): 0.20, 0.66], p = 0.0009, (9 RCTs)}, late onset sepsis [RR: 0.56 (95% CI: 0.45, 0.71), p < 0.00001, (7 RCTs)] and mortality [RR: 0.62 (95% CI: 0.41, 0.95, p = 0.03 (8 RCTs)] in the probiotic group. Probiotics also reduced the time to full feeds [Mean difference (MD): -4.09 d (95% CI: -4.52, -3.65), p < 0.00001, 5 RCTs] and duration of hospital stay [Fixed effects model (FEM): MD: -2.00 d (95% CI: -2.46, -1.53), p < 0.00001, 6 RCTs]. Current evidence from RCTs supports probiotic supplementation for optimizing outcomes of preterm infants in India.

Intranasal fentanyl for pain management during screening for retinopathy of prematurity in preterm infants: a randomized controlled trial.

OBJECTIVE: To study the efficacy of intranasal fentanyl as an adjunct for pain management during screening for retinopathy of prematurity (ROP) in preterm infants. STUDY DESIGN: In 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. RESULTS: A 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. CONCLUSION: Intranasal 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 REGISTRATION: CTRI/2017/12/011016.