Inhaled bronchodilators for the prevention and treatment of chronic lung disease in preterm infants.

BACKGROUND: Chronic lung disease (CLD) occurs frequently in preterm infants and is associated with respiratory morbidity. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increased compliance and tidal volume, and decreased airway resistance, have been documented with the use of bronchodilators in infants with CLD. Therefore, bronchodilators are widely considered to have a role in the prevention and treatment of CLD, but there remains uncertainty as to whether they improve clinical outcomes. This is an update of the 2016 Cochrane review. OBJECTIVES: To determine the effect of inhaled bronchodilators given as prophylaxis or as treatment for chronic lung disease (CLD) on mortality and other complications of preterm birth in infants at risk for or identified as having CLD. SEARCH METHODS: An Information Specialist searched CENTRAL, MEDLINE, Embase, CINAHL and three trials registers from 2016 to May 2023. In addition, the review authors undertook reference checking, citation searching and contact with trial authors to identify additional studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials involving preterm infants less than 32 weeks old that compared bronchodilators to no intervention or placebo. CLD was defined as oxygen dependency at 28 days of life or at 36 weeks' postmenstrual age. Initiation of bronchodilator therapy for the prevention of CLD had to occur within two weeks of birth. Treatment of infants with CLD had to be initiated before discharge from the neonatal unit. The intervention had to include administration of a bronchodilator by nebulisation or metered dose inhaler. The comparator was no intervention or placebo. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Critical outcomes included: mortality within the trial period; CLD (defined as oxygen dependency at 28 days of life or at 36 weeks' postmenstrual age); adverse effects of bronchodilators, including hypokalaemia (low potassium levels in the blood), tachycardia, cardiac arrhythmia, tremor, hypertension and hyperglycaemia (high blood sugar); and pneumothorax. We used the GRADE approach to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included two randomised controlled trials in this review update. Only one trial provided useable outcome data. This trial was conducted in six neonatal intensive care units in France and Portugal, and involved 173 participants with a gestational age of less than 31 weeks. The infants in the intervention group received salbutamol for the prevention of CLD. The evidence suggests that salbutamol may result in little to no difference in mortality (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.50 to 2.31; risk difference (RD) 0.01, 95% CI -0.09 to 0.11; low-certainty evidence) or CLD at 28 days (RR 1.03, 95% CI 0.78 to 1.37; RD 0.02, 95% CI -0.13 to 0.17; low-certainty evidence), when compared to placebo. The evidence is very uncertain about the effect of salbutamol on pneumothorax. The one trial with usable data reported that there were no relevant differences between groups, without providing the number of events (very low-certainty evidence). Investigators in this study did not report if side effects occurred. We found no eligible trials that evaluated the use of bronchodilator therapy for the treatment of infants with CLD. We identified no ongoing studies. AUTHORS' CONCLUSIONS: Low-certainty evidence from one trial showed that inhaled bronchodilator prophylaxis may result in little or no difference in the incidence of mortality or CLD in preterm infants, when compared to placebo. The evidence is very uncertain about the effect of salbutamol on pneumothorax, and neither included study reported on the incidence of serious adverse effects. We identified no trials that studied the use of bronchodilator therapy for the treatment of CLD. Additional clinical trials are necessary to assess the role of bronchodilator agents in the prophylaxis or treatment of CLD. Researchers studying the effects of inhaled bronchodilators in preterm infants should include relevant clinical outcomes in addition to pulmonary mechanical outcomes.

Plant-Derived Substances for Prevention of Necrotising Enterocolitis: A Systematic Review of Animal Studies.

Inflammation, oxidative injury, and gut dysbiosis play an important role in the pathogenesis of necrotising enterocolitis (NEC). Plant-derived substances have historically been used as therapeutic agents due to their anti-inflammatory, antioxidant, and antimicrobial properties. We aimed to review pre-clinical evidence for plant-derived substances in the prevention and treatment of NEC. A systematic review was conducted using the following databases: PubMed, EMBASE, EMCARE, MEDLINE and Cochrane Library (PROSPERO CRD42022365477). Randomized controlled trials (RCTs) and quasi-RCTs that evaluated a plant-derived substance as an intervention for NEC in an animal model of the illness and compared pre-stated outcomes (e.g., clinical severity, severity of intestinal injury, mortality, laboratory markers of inflammation and oxidative injury) were included. Sixteen studies (n = 610) were included in the systematic review. Ten of the sixteen included RCTs (Preterm rat pups: 15, Mice: 1) reported mortality and all reported NEC-related histology. Meta-analysis showed decreased mortality [12/134 vs. 27/135; RR: 0.48 (95% CI: 0.26 to 0.87); p = 0.02, 10 RCTs] and decreased NEC in the experimental group [24/126 vs. 55/79; RR: 0.34 (95% CI: 0.22 to 0.52); p < 0.001, 6 RCTs]. Markers of inflammation (n = 11) and oxidative stress (n = 13) improved in all the studies that have reported this outcome. There was no significant publication bias for the outcome of mortality. Plant-derived substances have the potential to reduce the incidence and severity of histologically diagnosed NEC and mortality in rodent models. These findings are helpful in guiding further pre-clinical studies towards developing a food supplement for the prevention of NEC in preterm infants.

The role of nutrition in analysis of risk factors and short-term outcomes for late-onset necrotizing enterocolitis among very preterm infants: a nationwide, multicenter study in China.

BACKGROUND: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times. METHOD: Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups. RESULTS: Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation. CONCLUSION: Actively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs. TRIAL REGISTRATION: ChiCTR1900023418 (26/05/2019).

Association of antenatal corticosteroids with mortality and morbidities in very preterm infants born to women with hypertensive disorders of pregnancy: a multicenter prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) is the most common cause of indicated preterm delivery, but the impact of prenatal steroid exposure on the outcomes of preterm infants born to HDP mothers, who may be at risk for intrauterine hypoxia-ischemia, remains uncertain. The study objective is to evaluate the mortality and morbidities in HDP for very preterm infants (VPIs) exposed to different course of ANS. METHODS: This is a prospective cohort study comprising infants with < 32 weeks gestation born to women with HDP only from 1 Jan. 2019 to 31 Dec. 2021 within 40 participating neonatal intensive care units (NICUs) in Sino-northern network. ANS courses included completed, partial, repeated, and no ANS. Univariate and multivariable analyses were performed on administration of ANS and short-term outcomes before discharge. RESULTS: Among 1917 VPIs born to women with HDP only, 987(51.4%) received a complete course of ANS within 48 h to 7 days before birth, 560(29.2%) received partial ANS within 24 h before delivery, 100(5.2%) received repeat ANS and 270 (14.1%) did not receive any ANS. Compared to infants who received complete ANS, infants unexposed to ANS was associated with higher odds of death (AOR 1.85; 95%CI 1.10, 3.14), Severe Neurological Injury (SNI) or death (AOR 1.68; 95%CI 1.29,3.80) and NEC or death (AOR 1.78; 95%CI 1.55, 2.89), the repeated ANS group exhibits a significant negative correlation with the duration of oxygen therapy days (correlation coefficient - 18.3; 95%CI-39.2, -2.1). However, there were no significant differences observed between the full course and partial course groups in terms of outcomes. We can draw similar conclusions in the non-SGA group, while the differences are not significant in the SGA group. From KM curve, it showed that the repeated group had the highest survival rate, but the statistical analysis did not indicate a significant difference. CONCLUSIONS: Even partial courses of ANS administered within 24 h before delivery proved to be protective against death and other morbidities. The differences mentioned above are more pronounced in the non-SGA group. Repeat courses demonstrate a trend toward protection, but this still needs to be confirmed by larger samples.

A Quality Improvement Initiative to Reduce Necrotizing Enterocolitis in Very Preterm Infants.

OBJECTIVE: To reduce the incidence of necrotizing enterocolitis (NEC) among very preterm infants in the Calgary Health Region to ≤2% within 2 years. METHODS: A multidisciplinary team developed key drivers for NEC. Targeted interventions included strategies to increase mothers' own milk (MOM), improve compliance with feeding regimens, standardize management of feeding intolerance, prevent intestinal microbial aberrations, and feed conservatively during blood transfusion and the treatment of patent ductus arteriosus. The outcome measure was NEC (≥ stage 2). Changes in NEC rates were examined among racial and ethnic groups. Process measures included MOM feeding at discharge, the difference between actual and expected time to reach full feeds, lowest hemoglobin, and the duration of empirical antibiotics. Growth, the rate of blood transfusion, and the duration of parenteral nutrition were balancing measures. The preintervention, intervention, and sustainment periods were January 2013 to June 2016, July 2016 to December 2018, and December 2018 to December 2021, respectively. RESULTS: We included 2787 infants born at ≤326/7 weeks' gestation (1105 preintervention, 763 during intervention, and 919 in sustainment). NEC decreased from 5.6% to 1.9%. Process measures indicated increased MOM feeding at discharge, improved compliance with feeding regimens, increased lowest hemoglobin levels, and shorter durations of empirical antibiotics. Balancing measures revealed improved weight Z-scores, shorter durations on parenteral nutrition, and increased rates of blood transfusion. CONCLUSIONS: Quality improvement initiatives to increase MOM, improve compliance with feeding regimens, feed conservatively during blood transfusion and treatment of patent ductus arteriosus, and prevent intestinal microbial aberrations were associated with reduced NEC.

Postnatal Corticosteroids To Prevent Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a common, severe chronic respiratory disease that affects very preterm infants. In utero and postnatal exposure to proinflammatory stimuli contribute to the pathophysiology of BPD. Corticosteroids, because of their potent anti-inflammatory properties, may decrease respiratory morbidity and reduce the risk of BPD in very preterm infants. However, these medications can have adverse effects on the developing brain and other organ systems. This review examines current evidence on the risks and benefits of postnatal corticosteroids used to prevent BPD in preterm infants.

Effect of SMOF lipid emulsion on physical growth and extrauterine growth retardation in very preterm infants: Insights from a multicenter retrospective cohort study.

OBJECTIVE: The aim of this study was to investigate the effects of soybean, medium-chain triacylglycerols (MCTs), olive oil, and fish oil (SMOF) on short-term clinical outcomes, physical growth, and extrauterine growth retardation (EUGR) in very preterm infants. METHODS: This was a multicenter retrospective cohort study of very preterm infants hospitalized in neonatal intensive care units at five tertiary hospitals in China between January 2021 and December 2021. According to the type of fat emulsion used in parenteral nutrition (PN), eligible very preterm infants were divided into the MCTs/long-chain triacylglycerol (MCT/LCT) group and SMOF group. Change in weight z-score (weight Δz) between measurements at birth and at 36 wk of postmenstrual age or at discharge, the incidence of EUGR, and short-term clinical outcomes between the two groups were compared and analyzed. RESULTS: We enrolled 409 very preterm infants, including 205 in the MCT/LCT group and 204 in the SMOF group. Univariate analysis showed that infants in the SMOF group had significantly longer duration of invasive mechanical ventilation and PN, longer days to reach total enteral nutrition, and a higher proportion of maximum weight loss than those in MCT/LCT group (all P < 0.05). After adjusting for the confounding variables, multifactorial logistic regression analysis of short-term clinical outcomes showed that SMOF had protective effects on PN-associated cholestasis (odds ratio [OR], 0.470; 95% confidence interval [CI], 0.266-0.831) and metabolic bone disease of prematurity (OR, 0.263; 95% CI, 0.078-0.880). Additionally, SMOF was an independent risk factor for lower weight growth velocity (ß = -0.733; 95% CI, -1.452 to -0.015) but had no effect on the incidence of EUGR (OR, 1.567; 95% CI, 0.912 to -2.693). CONCLUSION: Compared with MCT/LCT, SMOF can reduce the risk for PN-associated cholestasis and metabolic bone disease of prematurity in very preterm infants and has a negative effect on growth velocity but has no effect on the incidence of EUGR.

An Update on Lung Function of Extremely and Very Preterm Infants in Later Life: The Role of Early Nutritional Interventions.

Birth occurring at ≤32 weeks' gestation ("very preterm") or at ≤28 weeks' gestation ("extremely preterm") potentially poses considerable health problems for the neonate, including respiratory sequelae, not only during the immediate newborn period, but throughout childhood and into adulthood. With the progressive improvements in neonatal care, the survival of extremely preterm and very preterm neonates has improved substantially. However, a considerable percentage of these infants suffer dysfunctions that may trigger, at some stage later in life, the onset of respiratory morbidities. The interruption of the normal development of the respiratory tract caused by preterm birth, in combination with postnatal lung injury caused by various interventions, e.g., mechanical ventilation and oxygen therapy, increases the risk ofthe development of long-term respiratory deficits in survivors. Those infants that are most affected are those who develop chronic lung disease of prematurity (also called bronchopulmonary dysplasia, BPD), but impaired lung function can develop irrespective of BPD diagnosis. Apart from indicating abnormal lung function in survivors of extreme prematurity, recent long-term follow-up studies also emphasize the crucial role of early nutritional intake as an effective strategy, which promotes lung growth and repair. This article will update the associations between extremely/very preterm birth with long-term respiratory outcomes. It will also discuss the protective effect of nutritional interventions, focusing on recently published follow-up data.

Antenatal Neuroprotective Magnesium Sulfate in Very Preterm Infants and Its Association With Feeding Intolerance.

INTRODUCTION/OBJECTIVE: Magnesium sulfate (MgSO 4 ) treatment is widely used for fetal neuroprotection despite the controversy concerning the side effects. There is limited data regarding the impact of various cumulative maternal doses and neonatal serum magnesium (Mg) levels on short-term neonatal morbidity and mortality. We opted to carry out a study to determine the impact of neonatal serum Mg levels on neonatal outcomes. METHOD: We conducted this prospective observational study between 2017 and 2021. Antenatal MgSO 4 was used for neuroprotective purpose only during the study period. Inborn preterm infants delivered between 23 and 31 6/7 weeks of gestation were enrolled consecutively. Babies who underwent advanced resuscitation in the delivery room, inotropic treatment due to hemodynamic instability in the first 7 days of life, >12 hours since the discontinuation of maternal MgSO 4 treatment, severe anemia, and major congenital/chromosomal anomalies were excluded from the study. The subgroup of babies with serum Mg level at the 6th hour of life underwent an analysis. A neonatal Mg concentration of 2.5 mg/dL was used to classify MgSO 4 -exposed patients into 2 groups (<2.5 mg/dL and ≥2.5 mg/dL). Another analysis was performed between babies whose mothers were exposed to MgSO 4 and those not exposed. Finally, the groups' neonatal outcomes were compared. RESULTS: Of the 584 babies, 310 received antenatal MgSO 4 . The birth weights were significantly lower in the MgSO 4 exposed group (1113 ± 361 g vs 1202 ± 388 g, P = 0.005). Antenatal corticosteroid usage and intrauterine growth restriction were also noted to be higher. The MgSO 4 group was more likely to have bronchopulmonary dysplasia, prolonged invasive ventilation, necrotizing enterocolitis, delayed enteral nutrition, and feeding intolerance ( P < 0.05). MgSO 4 treatment was shown as an independent risk factor for feeding intolerance when corrected for confounders (odds ratio 2.13, 95% confidence interval: 1.4-3.1, P = 0.001). Furthermore, serum Mg level significantly correlated with feeding intolerance ( r = 0.21, P = 0.002). CONCLUSION: This study highlighted the effect of MgSO 4 treatment and the potential superiority of serum Mg level as a predictor of immediate neonatal outcomes, particularly delayed enteral nutrition and feeding intolerance. Further studies are warranted to ascertain the optimal serum Mg concentration of preterm infants in early life to provide maximum benefit with minimal side effects.

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity in very preterm or VLBW infants. OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and associated mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the Maternity and Infant Care database, and CINAHL from inception to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing probiotics with placebo or no probiotics in very preterm infants (born before 32 weeks' gestation) and VLBW infants (weighing less than 1500 g at birth). DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with associated 95% confidence intervals (CIs). The primary outcomes were NEC and all-cause mortality; secondary outcome measures were late-onset invasive infection (more than 48 hours after birth), duration of hospitalisation from birth, and neurodevelopmental impairment. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 60 trials with 11,156 infants. Most trials were small (median sample size 145 infants). The main potential sources of bias were unclear reporting of methods for concealing allocation and masking caregivers or investigators in about half of the trials. The formulation of the probiotics varied across trials. The most common preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., andStreptococcus spp., alone or in combination. Very preterm or very low birth weight infants Probiotics may reduce the risk of NEC (RR 0.54, 95% CI 0.46 to 0.65; I² = 17%; 57 trials, 10,918 infants; low certainty). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI 25 to 50). Probiotics probably reduce mortality slightly (RR 0.77, 95% CI 0.66 to 0.90; I² = 0%; 54 trials, 10,484 infants; moderate certainty); the NNTB was 50 (95% CI 50 to 100). Probiotics probably have little or no effect on the risk of late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; I² = 22%; 49 trials, 9876 infants; moderate certainty). Probiotics may have little or no effect on neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26; I² = 0%; 5 trials, 1518 infants; low certainty). Extremely preterm or extremely low birth weight infants Few data were available for extremely preterm or extremely low birth weight (ELBW) infants. In this population, probiotics may have little or no effect on NEC (RR 0.92, 95% CI 0.69 to 1.22, I² = 0%; 10 trials, 1836 infants; low certainty), all-cause mortality (RR 0.92, 95% CI 0.72 to 1.18; I² = 0%; 7 trials, 1723 infants; low certainty), or late-onset invasive infection (RR 0.93, 95% CI 0.78 to 1.09; I² = 0%; 7 trials, 1533 infants; low certainty). No trials provided data for measures of neurodevelopmental impairment in extremely preterm or ELBW infants. AUTHORS' CONCLUSIONS: Given the low to moderate certainty of evidence for the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or VLBW infants, and particularly for extremely preterm or ELBW infants, there is a need for further large, high-quality trials to provide evidence of sufficient validity and applicability to inform policy and practice.

Risk factors for periventricular-intraventricular haemorrhage severity in preterm infants: a propensity score-matched analysis.

BACKGROUND: Most previous studies comparing etiological studies in infants with and without periventricular-intraventricular haemorrhage (PV-IVH) concluded that younger gestational age (GA) was associated with a higher prevalence rate of PV-IVH. However, only a few studies have examined the risk factors associated with the severity of PV-IVH after removing the influence of GA. Therefore, we investigated the risk factors apart from GA for PV-IVH severity in preterm infants less than 28 weeks. METHODS: This was a retrospective case-control study of preterm infants born in West China Second Hospital with PV-IVH between 2009 and 2020. PV-IVH was defined using cranial ultrasound screening. Preterm infants were divided into no PV-IVH and PV-IVH groups, and preterm infants with PV-IVH were divided into mild and severe PV-IVH groups. Groups were matched in a 1:1 ratio using propensity score calculated from GA. Variables were collected from infant-mother pairs. A stepwise forward multivariate logistic regression model was adopted to select factors that affected PV-IVH in preterm infants. RESULTS: A total of 429 preterm infants were included. The total incidence of PV-IVH in preterm infants was 55.6%, and the incidence of mild and severe PV-IVH was 28.7% and 26.9%, respectively. We matched 162 infants with no PV-IVH with 162 infants with PV-IVH. The results suggested that electrolyte disorder (OR 2.79, 95% CI: 1.34-5.77), early-onset sepsis (OR 1.76, 95% CI: 1.01-3.08), thrombocytopenia (OR 2.87, 95% CI: 1.10-7.48), invasive mechanical ventilation (OR 4.21, 95% CI: 1.86-9.55), and male sex (OR 2.16, 95% CI: 1.29-3.60) were independently associated with PV-IVH. Then, we matched 87 infants with mild PV-IVH with 87 infants with severe PV-IVH. The results suggested that electrolyte disorder (OR 2.88, 95% CI: 1.29-6.45), thrombocytopenia (OR 5.73, 95% CI: 1.91-17.14), and invasive mechanical ventilation (OR 10.54, 95% CI: 1.16-95.85) were independently associated with severity of PV-IVH. CONCLUSIONS: Regardless of GA, electrolyte disorder, early-onset sepsis, thrombocytopenia, invasive mechanical ventilation, and male sex contributed to PV-IVH in preterm infants, and electrolyte disorder, thrombocytopenia, and invasive mechanical ventilation contributed to severe PV-IVH. These risk factors may combine to predict the incidence of PV-IVH in preterm infants.

Prebiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Dietary supplementation with prebiotic oligosaccharides to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or very low birth weight (VLBW) infants. OBJECTIVES: To assess the benefits and harms of enteral supplementation with prebiotics (versus placebo or no treatment) for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care database and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing prebiotics with placebo or no prebiotics in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. The primary outcomes were NEC and all-cause mortality, and the secondary outcomes were late-onset invasive infection, duration of hospitalisation since birth, and neurodevelopmental impairment. DATA COLLECTION AND ANALYSIS: Two review authors separately evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference (MD), with associated 95% confidence intervals (CIs). The primary outcomes of interest were NEC and all-cause mortality; our secondary outcome measures were late-onset (> 48 hours after birth) invasive infection, duration of hospitalisation, and neurodevelopmental impairment. We used the GRADE approach to assess the level of certainty of the evidence. MAIN RESULTS: We included seven trials in which a total of 705 infants participated. All the trials were small (mean sample size 100). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were potential sources of bias in three of the trials. The studied prebiotics were fructo- and galacto-oligosaccharides, inulin, and lactulose, typically administered daily with enteral feeds during birth hospitalisation. Meta-analyses of data from seven trials (686 infants) suggest that prebiotics may result in little or no difference in NEC (RR 0.97, 95% CI 0.60 to 1.56; RD none fewer per 1000, 95% CI 50 fewer to 40 more; low-certainty evidence), all-cause mortality (RR 0.43, 95% CI 0.20 to 0.92; 40 per 1000 fewer, 95% CI 70 fewer to none fewer; low-certainty evidence), or late-onset invasive infection (RR 0.79, 95% CI 0.60 to 1.06; 50 per 1000 fewer, 95% CI 100 fewer to 10 more; low-certainty evidence) prior to hospital discharge. The certainty of this evidence is low because of concerns about the risk of bias in some trials and the imprecision of the effect size estimates. The data available from one trial provided only very low-certainty evidence about the effect of prebiotics on measures of neurodevelopmental impairment (Bayley Scales of Infant Development (BSID) Mental Development Index score < 85: RR 0.84, 95% CI 0.25 to 2.90; very low-certainty evidence; BSID Psychomotor Development Index score < 85: RR 0.24, 95% 0.03 to 2.00; very low-certainty evidence; cerebral palsy: RR 0.35, 95% CI 0.01 to 8.35; very low-certainty evidence). AUTHORS' CONCLUSIONS: The available trial data provide low-certainty evidence about the effects of prebiotics on the risk of NEC, all-cause mortality before discharge, and invasive infection, and very low-certainty evidence about the effect on neurodevelopmental impairment for very preterm or VLBW infants. Our confidence in the effect estimates is limited; the true effects may be substantially different. Large, high-quality trials are needed to provide evidence of sufficient validity to inform policy and practice decisions.

Routine monitoring of gastric residual for prevention of necrotising enterocolitis in preterm infants.

BACKGROUND: Routine monitoring of gastric residual in preterm infants on gavage feeds is a common practice used to guide initiation and advancement of feeds. It is believed that an increase in or an altered gastric residual may be predictive of necrotising enterocolitis (NEC). Withholding monitoring of gastric residual may take away the early indicator and thus may increase the risk of NEC. However, routine monitoring of gastric residual as a guide, in the absence of uniform standards, may lead to unnecessary delay in initiation and advancement of feeds and hence might result in a delay in establishing full enteral feeds. This in turn may increase the duration of total parenteral nutrition (TPN) and central venous line usage, increasing the risk of associated complications. Furthermore, delays in establishing full enteral feeds increase the risk of extrauterine growth restriction and neurodevelopmental impairment. OBJECTIVES: • To assess the efficacy and safety of routine monitoring versus no monitoring of gastric residual in preterm infants • To assess the efficacy and safety of routine monitoring of gastric residual based on two different criteria for interrupting feeds or decreasing feed volume in preterm infants SEARCH METHODS: We conducted searches in Cochrane CENTRAL via CRS, Ovid MEDLINE, Embase and CINAHL in February 2022. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs), quasi- and cluster-RCTs. SELECTION CRITERIA: We selected RCTs that compared routine monitoring versus no monitoring of gastric residual and trials that used two different criteria for gastric residual to interrupt feeds in preterm infants. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, risk of bias and extracted data. We analysed treatment effects in individual trials and reported risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence intervals (CI). We calculated the number needed to treat for an additional beneficial/harmful outcome (NNTB/NNTH) for dichotomous outcomes with significant results. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included five studies (423 infants) in this updated review. Routine monitoring versus no routine monitoring of gastric residual in preterm infants Four RCTs with 336 preterm infants met the inclusion criteria for this comparison. Three studies were performed in infants with birth weight of < 1500 g, while one study included infants with birth weight between 750 g and 2000 g. The trials were unmasked but were otherwise of good methodological quality. Routine monitoring of gastric residual:  - probably has little or no effect on the risk of NEC (RR 1.08, 95% CI 0.46 to 2.57; 334 participants, 4 studies; moderate-certainty evidence); - probably increases the time to establish full enteral feeds (MD 3.14 days, 95% CI 1.93 to 4.36; 334 participants, 4 studies; moderate-certainty evidence); - may increase the time to regain birth weight (MD 1.70 days, 95% CI 0.01 to 3.39; 80 participants, 1 study; low-certainty evidence);  - may increase the number of infants with feed interruption episodes (RR 2.21, 95% CI 1.53 to 3.20; NNTH 3, 95% CI 2 to 5; 191 participants, 3 studies; low-certainty evidence);  - probably increases the number of TPN days (MD 2.57 days, 95% CI 1.20 to 3.95; 334 participants, 4 studies; moderate-certainty evidence); - probably increases the risk of invasive infection (RR 1.50, 95% CI 1.02 to 2.19; NNTH 10, 95% CI 5 to 100; 334 participants, 4 studies; moderate-certainty evidence); - may result in little or no difference in all-cause mortality before hospital discharge (RR 2.14, 95% CI 0.77 to 5.97; 273 participants, 3 studies; low-certainty evidence). Quality and volume of gastric residual compared to quality of gastric residual alone for feed interruption in preterm infants One trial with 87 preterm infants met the inclusion criteria for this comparison. The trial included infants with 1500 g to 2000 g birth weight.  Using two different criteria of gastric residual for feed interruption: - may result in little or no difference in the incidence of NEC (RR 5.35, 95% CI 0.26 to 108.27; 87 participants; low-certainty evidence);  - may result in little or no difference in time to establish full enteral feeds (MD -0.10 days, 95% CI -0.91 to 0.71; 87 participants; low-certainty evidence); - may result in little or no difference in time to regain birth weight (MD 1.00 days, 95% CI -0.37 to 2.37; 87 participants; low-certainty evidence); - may result in little or no difference in number of TPN days (MD 0.80 days, 95% CI -0.78 to 2.38; 87 participants; low-certainty evidence); - may result in little or no difference in the risk of invasive infection (RR 5.35, 95% CI 0.26 to 108.27; 87 participants; low-certainty evidence); - may result in little or no difference in all-cause mortality before hospital discharge (RR 3.21, 95% CI 0.13 to 76.67; 87 participants; low-certainty evidence).  - we are uncertain about the effect of using two different criteria of gastric residual on the risk of feed interruption episodes (RR 3.21, 95% CI 0.13 to 76.67; 87 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests routine monitoring of gastric residual has little or no effect on the incidence of NEC. Moderate-certainty evidence suggests monitoring gastric residual probably increases the time to establish full enteral feeds, the number of TPN days and the risk of invasive infection. Low-certainty evidence suggests monitoring gastric residual may increase the time to regain birth weight and the number of feed interruption episodes, and may have little or no effect on all-cause mortality before hospital discharge. Further RCTs are warranted to assess the effect on long-term growth and neurodevelopmental outcomes.

Effectiveness of a probiotic combination on the neurodevelopment of the very premature infant.

Probiotics have shown a benefit in reducing necrotising enterocolitis in the premature infant, however the study of their effect on premature neonates' neurodevelopment is limited. The aim of our study was to elucidate whether the effect of Bifidobacterium bifidum NCDO 2203 combined with Lactobacillus acidophilus NCDO 1748 could positively impact the neurodevelopment of the preterm neonates. Quasi-experimental comparative study with a combined treatment of probiotics in premature infants < 32 weeks and < 1500 g birth weight, cared for at a level III neonatal unit. The probiotic combination was administered orally to neonates surviving beyond 7 days of life, until 34 weeks postmenstrual age or discharge. Globally, neurodevelopment was evaluated at 24 months corrected age. A total of 233 neonates were recruited, 109 in the probiotic group and 124 in the non-probiotic group. In those neonates receiving probiotics, there was a significant reduction in neurodevelopment impairment at 2 years of age RR 0.30 [0.16-0.58], and a reduction in the degree of impairment (normal-mild vs moderate-severe, RR 0.22 [0.07-0.73]). Additionally, there was a significant reduction in late-onset sepsis (RR 0.45 [0.21-0.99]). The prophylactic use of this probiotic combination contributed to improving neurodevelopmental outcome and reduced sepsis in neonates born at < 32 weeks and < 1500 g.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured abstract. Please check and confirm.Accepted.

Early psychomotor therapy in very preterm infants does not improve Bayley-III scales at 2 years.

AIM: To assess the efficacy of post-hospital psychomotor therapy in the development of very preterm infants at nine and 24 months. METHODS: We conducted a randomised controlled study at Toulouse Children's Hospital between 2008 and 2014 among preterm infants aged under 30 weeks. All infants in both groups could benefitt from physiotherapy to prevent motor disorders. The intervention group received 20 early post-hospital psychomotor therapy sessions. The development was assessed by the Bayley Scale Infant Development at nine and 24 months. RESULTS: The intervention and control group contained 77 and 84 infants, respectively, with 57 infants in each group undergoing assessment at 24 months. Boys accounted for 56% of the population. Median gestational age was 28 weeks, range 25-29. The development scores at 24 months did not significantly differ between the randomisation groups. At 9 months, we observed improvements in global motricity (mean difference 0.9 point, p = 0.04) and fine motricity for the subgroup containing educationally underserved mothers (mean difference 1.6 point, p = 0.008). There was no significant difference in neuromotor functioning between the two groups. CONCLUSION: The benefits of psychomotor therapy were short-lived and did not persist post-intervention. Our results and this organisational model encouraged us to persevere towards similar multi-professional care.

Bovine colostrum as a fortifier to human milk in very preterm infants - A randomized controlled trial (FortiColos).

BACKGROUND: Human milk for very preterm infants need fortification for optimal growth and development but the optimal fortification product remains to be identified. AIMS: To investigate feasibility, safety and preliminary efficacy on growth and blood biochemistry when using intact bovine colostrum (BC) as a fortifier to human milk in very preterm infants. METHODS: In an open-label, multicenter, randomized controlled pilot trial (infants 26-31 weeks' gestation), mother's own milk or donor human milk was fortified with powdered BC (n = 115) or a conventional fortifier (CF, bovine-milk-based, n = 117) until 35 weeks' postmenstrual age. Fortifiers and additional micronutrients were added to human milk according to local guidelines to achieve optimal growth (additional protein up to +1.4 g protein/100 mL human milk). Anthropometry was recorded weekly. Clinical morbidities including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) were recorded. Clinical biochemistry included plasma amino acid (AA) levels to assess protein metabolic responses to the new fortifier. RESULTS: A total of 232 infants, gestational age (GA) 28.5 ± 1.4 (weeks + days), fulfilled inclusion criteria. Birthweight, GA and delta Z scores from birth to end of intervention on weight, length or head circumference did not differ between groups, nor between the subgroups of small for gestational age infants. Likewise, incidence of NEC (BC: 3/115 vs. CF: 5/117, p = 0.72, unadjusted values), LOS (BC: 23/113 vs. CF: 14/116, p = 0.08) and other morbidities did not differ. BC infants received more protein than CF infants (+10%, p < 0.05) and showed several elevated AA levels (+10-40%, p < 0.05). CONCLUSION: Infants fortified with BC showed similar growth but received more protein and showed a moderate increase in plasma AA-levels, compared with CF. Adjustments in protein composition and micronutrients in BC-based fortifiers may be required to fully suit the needs for very preterm infants.

Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants.

BACKGROUND: Intraventricular haemorrhage (IVH) is a major complication of preterm birth. Large haemorrhages are associated with a high risk of disability and hydrocephalus. Instability of blood pressure and cerebral blood in the newborn flow are postulated as causative factors. Another mechanism may involve reperfusion damage from oxygen free radicals. It has been suggested that phenobarbital stabilises blood pressure and may protect against free radicals. This is an update of a review first published in 2001 and updated in 2007 and 2013. OBJECTIVES: To assess the benefits and harms of the postnatal administration of phenobarbital in preterm infants at risk of developing IVH compared to control (i.e. no intervention or placebo). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL and clinical trial registries in January 2022. A new, more sensitive search strategy was developed, and searches were conducted without date limits.  SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs in which phenobarbital was given within the first 24 hours of life to preterm infants identified as being at risk of IVH because of gestational age below 34 weeks, birth weight below 1500 g or respiratory failure. Phenobarbital was compared to no intervention or placebo. We excluded infants with serious congenital malformations. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were all grades of IVH and severe IVH (i.e. grade III and IV); secondary outcomes were ventricular dilation or hydrocephalus, hypotension, pneumothorax, hypercapnia, acidosis, mechanical ventilation, neurodevelopmental impairment and death. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 10 RCTs (792 infants). The evidence suggests that phenobarbital results in little to no difference in the incidence of IVH of any grade compared with control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.84 to 1.19; risk difference (RD) 0.00, 95% CI -0.06 to 0.07; I² for RD = 65%; 10 RCTs, 792 participants; low certainty evidence) and in severe IVH (RR 0.88, 95% CI 0.64 to 1.21; 10 RCTs, 792 participants; low certainty evidence). The evidence is very uncertain about the effect of phenobarbital on posthaemorrhagic ventricular dilation or hydrocephalus (RR 0.62, 95% CI 0.31 to 1.26; 4 RCTs, 271 participants; very low certainty evidence), mild neurodevelopmental impairment (RR 0.57, 95% CI 0.15 to 2.17; 1RCT, 101 participants; very low certainty evidence), and severe neurodevelopmental impairment (RR 1.12, 95% CI 0.44 to 2.82; 2 RCTs, 153 participants; very low certainty evidence). Phenobarbital may result in little to no difference in death before discharge (RR 0.88, 95% CI 0.64 to 1.21; 9 RCTs, 740 participants; low certainty evidence) and mortality during study period (RR 0.98, 95% CI 0.72 to 1.33; 10 RCTs, 792 participants; low certainty evidence) compared with control. We identified no ongoing trials. AUTHORS' CONCLUSIONS: The evidence suggests that phenobarbital results in little to no difference in the incidence of IVH (any grade or severe) compared with control (i.e. no intervention or placebo). The evidence is very uncertain about the effects of phenobarbital on ventricular dilation or hydrocephalus and on neurodevelopmental impairment. The evidence suggests that phenobarbital results in little to no difference in death before discharge and all deaths during the study period compared with control. Since 1993, no randomised studies have been published on phenobarbital for the prevention of IVH in preterm infants, and no trials are ongoing. The effects of postnatal phenobarbital might be assessed in infants with both neonatal seizures and IVH, in both randomised and observational studies. The assessment of benefits and harms should include long-term outcomes.

Neurodevelopmental Outcomes at Two Years' Corrected Age of Very Preterm Infants after Implementation of a Post-Discharge Responsive Parenting Intervention Program (TOP Program).

OBJECTIVE: To compare neurodevelopmental outcomes at 2 years corrected age (CA) between infants born very preterm (VP) who did or did not receive a postdischarge responsive parenting intervention (Transmural developmental support for very preterm infants and their parents [TOP program]) between discharge home and 12 months' CA. STUDY DESIGN: The Systemic Hydrocortisone to Prevent Bronchopulmonary Dysplasia (SToP-BPD) study showed no differences between treatment groups in motor and cognitive development using the Dutch Bayley Scales of Infant Development and behavior using the Child Behavior Checklist at 2 years' CA. During its study period, the TOP program was gradually scaled up nationwide in the same population, providing an opportunity to evaluate the effect of this program on neurodevelopmental outcome, after adjusting for baseline differences. RESULTS: Among 262 surviving VP infants in the SToP-BPD study, 35% received the TOP program. Infants in the TOP group had a significantly lower incidence of a cognitive score <85 (20.3% vs 35.2%; adjusted absolute risk reduction: -14.1% [95% CI: -27.2 to -1.1]; P = .03), and a significantly higher mean cognitive score (96.7 ± 13.8), compared with the non-TOP group (92.0 ± 17.5; crude mean difference: 4.7 [95% CI: 0.3 to 9.2]; P = .03). No significant differences were found on motor scores. For behavior problems, a small but statistically significant effect for anxious/depressive problems was found in the TOP group (50.5 vs 51.2; P = .02). CONCLUSIONS: VP infants supported by the TOP program from discharge until 12 months' CA had better cognitive function at 2 years' CA. This study demonstrates a sustained positive effect of the TOP program in VP infants.

Probiotics to prevent necrotizing enterocolitis and reduce mortality in neonates: A meta-analysis.

BACKGROUND: Probiotics are gradually being used as a supplementation to prevent necrotizing enterocolitis (NEC) and reduce mortality in neonates. We performed an updated meta-analysis to systematically evaluate the efficacy and safety of prophylactic probiotic supplementation for preventing NEC. METHODS: The databases including PubMed, Embase, Scopus, Web of Science, and China National Knowledge Infrastructure were used to search the relevant articles. The latest retrieval date was up to December 2021. The meta-analysis was performed using Stata version 10.0. Finally, a total of 70 studies containing 8319 cases and 9283 controls were included. The strength of the association between the supplementation of probiotics and NEC was measured by risk ratios (RRs) with 95% confidence intervals (CIs). Pooled effect sizes across studies were performed by a random effect model. RESULTS: The results showed that the probiotics could significantly reduce the incidence of NEC (stage II or more) (RR = 0.436, 95% CI = 0.357-0.531, P < .001), the overall mortality (RR = 0.651, 95% CI = 0.506-0.836, P < .001), and NEC-related mortality (RR = 0.639, 95% CI = 0.423-0.966, P = .034). Due to the lack of sufficient sample size, we did not perform the subgroup analysis by types of probiotic strain. CONCLUSION: This meta-analysis indicates that the use of probiotics can effectively reduce the occurrence of NEC and mortality in neonates.

Stem cell-based interventions for the prevention and treatment of intraventricular haemorrhage and encephalopathy of prematurity in preterm infants.

BACKGROUND: Germinal matrix-intraventricular haemorrhage (GMH-IVH) and encephalopathy of prematurity (EoP) remain substantial issues in neonatal intensive care units worldwide. Current therapies to prevent or treat these conditions are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies. This is an update of the 2019 review, which did not include EoP. OBJECTIVES: To evaluate the benefits and harms of stem cell-based interventions for prevention or treatment of GM-IVH and EoP in preterm infants. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was April 2022. SELECTION CRITERIA: We attempted to include randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing 1. stem cell-based interventions versus control; 2. mesenchymal stromal cells (MSCs) of type or source versus MSCs of other type or source; 3. stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or 4. MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH or EoP; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH or with EoP. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. all-cause neonatal mortality, 2. major neurodevelopmental disability, 3. GM-IVH, 4. EoP, and 5. extension of pre-existing non-severe GM-IVH or EoP. We planned to use GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified no studies that met our inclusion criteria. Three studies are currently registered and ongoing. Phase 1 trials are described in the 'Excluded studies' section. AUTHORS' CONCLUSIONS: No evidence is currently available to evaluate the benefits and harms of stem cell-based interventions for treatment or prevention of GM-IVH or EoP in preterm infants. We identified three ongoing studies, with a sample size range from 20 to 200. In two studies, autologous cord blood mononuclear cells will be administered to extremely preterm infants via the intravenous route; in one, intracerebroventricular injection of MSCs will be administered to preterm infants up to 34 weeks' gestational age.