Development of Movement and Postural Patterns in Full-Term Infants Who Are at Low Risk in Belgium, India, Norway, and the United States.

OBJECTIVE: The objective of this study was to investigate the influences on motor development in infants who are at low risk from Belgium, India, Norway, and the United States (US) using the General Movement Assessment (GMA) at 10-16 weeks post-term age. METHODS: This was a cross-sectional study of prospectively enrolled full-term infants at low risk (n = 186). Certified GMA observers rated the fidgety movements, quality of the movement patterns, age-adequacy of the movement repertoire, postural patterns, movement character, and overall Motor Optimality Score - Revised (MOS-R). Scores were evaluated for associations with sex, birth weight category, gestational age, post-term age at video, and country. RESULTS: The majority of infants had normal fidgety movements (179/186, 96.2%). This did not vary by sex, birth weight, gestational age, post-term age at video, or country. All infants showed normal>atypical movement patterns. Variability was seen for age adequacy (optimal: 137/183, 74.9%), postural patterns (normal>atypical: 164/183, 89.6%), and smooth/ fluent movement character (138/183, 75.4%). Gestational age and post-term age at video were associated with atypical postural patterns but in multivariable regression, only younger post-term age retained significance (OR 2.94, 95% CI: 1.05-8.24). Lack of age adequacy was associated with post-term age (OR 13.15, 95% CI: 4.36-39.72), and country (compared with Norway; Belgium OR 3.38 95% CI:12.4-9.22; India OR 3.16, 95% CI:1.01-9.87: US not significant). Infants from India also showed lower rates of an optimal MOS-R (25-28) than infants from Norway. CONCLUSIONS: The normality and temporal organization of fidgety movements did not differ by sex, birth weight, post-term age, or country, suggesting that the fidgety movements are free of cultural and environmental influences. The majority of full-term infants who were healthy in this cohort showed normal scores for all aspects of motor development tested using the MOS-R. Differences in age adequacy and MOS-R by country warrant investigation with larger cohorts and longitudinal follow up. IMPACT STATEMENT: Understanding variations in typical motor development is essential to interpreting patterns of movement and posture in infants at risk for atypical development. Using the framework of Prechtl's General Movements Assessment, this study showed that the development of movement and posture in healthy infants were affected by age and country of birth, but the development of the fidgety movements appeared to be free of these influences. Local norms may be needed to interpret the Motor Optimality Score-Revised in all populations but further research on this topic is needed.

Late-Preterm Antenatal Steroids for Reduction of Neonatal Respiratory Complications: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy of antenatal corticosteroids in reducing neonatal respiratory complications when administered to those at risk of preterm delivery between 34 and 36 6/7 weeks of gestation. METHODS: This was a single-center, triple-blind, randomized, placebo-controlled trial in southern India enrolling pregnant participants at risk of preterm delivery between 34 and 36 6/7 weeks of gestation. Computer-generated block randomization was used with participants randomized to either one course of intramuscular betamethasone or placebo. The primary outcome was a composite of treatment for respiratory distress in the neonate, defined as need for oxygen or continuous positive airway pressure or mechanical ventilation for at least 2 hours in the first 72 hours of life. Neonatal secondary outcomes were transient tachypnea of the newborn, respiratory distress syndrome, necrotizing enterocolitis, sepsis, hyperbilirubinemia, hypoglycemia, stillbirth, and early neonatal death; maternal secondary outcomes were chorioamnionitis, postpartum hemorrhage, puerperal fever, and length of hospitalization. All analyses were based on intention to treat. A sample size of 1,200 was planned with 80% power to detect a 30% reduction in rates of respiratory distress. After a planned interim analysis, enrollment was stopped for futility. RESULTS: From March 2020 to August 2022, 847 participants were recruited, with 423 participants randomized to betamethasone and 424 participants randomized to placebo. There were 22 individuals lost to follow-up. There was no statistically significant difference in the primary outcome (betamethasone 4.9% vs placebo 4.8%, relative risk 1.03, 95% CI, 0.57-1.84, number needed to treat 786). There were no statistically significant differences in secondary neonatal or maternal outcomes. CONCLUSION: Betamethasone administered in the late-preterm period to those at risk for preterm delivery did not reduce the need for treatment of neonatal respiratory distress. CLINICAL TRIAL REGISTRATION: Clinical Trials Registry of India, CTRI/2019/09/021321.

Biochemical profiles and organ dysfunction in neonates with hypoxic-ischemic encephalopathy post-hoc analysis of the THIN trial.

BACKGROUND: Therapeutic hypothermia for infants with moderate to severe hypoxic-ischemic encephalopathy is well established as standard of care in high-income countries. Trials from low- and middle-income countries have shown contradictory results, and variations in the level of intensive care provided may partly explain these differences. We wished to evaluate biochemical profiles and clinical markers of organ dysfunction in cooled and non-cooled infants with moderate/severe hypoxic-ischemic encephalopathy. METHODS: This secondary analysis of the THIN (Therapeutic Hypothermia in India) study, a single center randomized controlled trial, included 50 infants with moderate to severe hypoxic-ischemic encephalopathy randomized to therapeutic hypothermia (n = 25) or standard care with normothermia (n = 25) between September 2013 and October 2015. Data were collected prospectively and compared by randomization groups. Main outcomes were metabolic acidosis, coagulopathies, renal function, and supportive treatments during the intervention. RESULTS: Cooled infants had lower pH than non-cooled infants at 6-12 h (median (IQR) 7.28 (7.20-7.32) vs 7.36 (7.31-7.40), respectively, p = 0.003) and 12-24 h (median (IQR) 7.30 (7.24-7.35) vs 7.41 (7.37-7.43), respectively, p < 0.001). Thrombocytopenia (< 100 000) was, though not statistically significant, twice as common in cooled compared to non-cooled infants (4/25 (16%) and 2/25 (8%), respectively, p = 0.67). No significant difference was found in the use of vasopressors (14/25 (56%) and 17/25 (68%), p = 0.38), intravenous bicarbonate (5/25 (20%) and 3/25 (12%), p = 0.70) or treatment with fresh frozen plasma (10/25 (40%) and 8/25 (32%), p = 0.56)) in cooled and non-cooled infants, respectively. Urine output < 1 ml/kg/h was less common in cooled infants compared to non-cooled infants at 0-24 h (7/25 (28%) vs. 16/23 (70%) respectively, p = 0.004). CONCLUSIONS: This post hoc analysis of the THIN study support that cooling of infants with hypoxic-ischemic encephalopathy in a level III neonatal intensive care unit in India was safe. Cooled infants had slightly lower pH, but better renal function during the first day compared to non-cooled infants. More research is needed to identify the necessary level of intensive care during cooling to guide further implementation of this neuroprotective treatment in low-resource settings. TRIAL REGISTRATION: Data from this article was collected during the THIN-study (Therapeutic Hypothermia in India; ref. CTRI/2013/05/003693 Clinical Trials Registry - India).

Estimating Preterm Lung Volume: A Comparison of Lung Ultrasound, Chest Radiography, and Oxygenation.

OBJECTIVE: To determine the relationship between lung ultrasound (LUS) examination, chest radiograph (CXR), and radiographic and clinical evaluations in the assessment of lung volume in preterm infants. STUDY DESIGN: In this prospective cohort study LUS was performed before CXR on 70 preterm infants and graded using (1) a LUS score, (2) an atelectasis score, and (3) measurement of atelectasis depth. Radiographic diaphragm position and radio-opacification were used to determine global and regional radiographic atelectasis. The relationship between LUS, CXR, and oxygenation was assessed using receiver operator characteristic and correlation analysis. RESULTS: LUS scores, atelectasis scores, and atelectasis depth did not correspond with radiographic global atelectasis (area under receiver operator characteristics curves, 0.54 [95% CI, 0.36-0.71], 0.49 [95% CI, 0.34-0.64], and 0.47 [95% CI, 0.31-0.64], respectively). Radiographic atelectasis of the right upper, right lower, left upper, and left lower quadrants was predicted by LUS scores (0.75 [95% CI, 0.59-0.92], 0.75 [95% CI, 0.62-0.89], 0.69 [95% CI, 0.56-0.82], and 0.63 [95% CI, 0.508-0.751]) and atelectasis depth (0.66 [95% CI, 0.54-0.78], 0.65 [95% CI, 0.53-0.77], 0.63 [95% CI, 0.50-0.76], and 0.56 [95% CI, 0.44-0.70]). LUS findings were moderately correlated with oxygen saturation index (ρ = 0.52 [95% CI, 0.30-0.70]) and saturation to fraction of inspired oxygen ratio (ρ = -0.63 [95% CI, -0.76 to -0.46]). The correlation between radiographic diaphragm position, the oxygenation saturation index, and peripheral oxygen saturation to fraction of inspired oxygen ratio was very weak (ρ = 0.36 [95% CI, 0.11-0.59] and ρ = -0.32 [95% CI, -0.53 to -0.07], respectively). CONCLUSIONS: LUS assessment of lung volume does not correspond with radiographic diaphragm position preterm infants. However, LUS predicted radiographic regional atelectasis and correlated with oxygenation. The relationship between radiographic diaphragm position and oxygenation was very weak. Although LUS may not replace all radiographic measures of lung volume, LUS more accurately reflects respiratory status in preterm infants. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12621001119886.

Early-onset neonatal seizures: lidocaine toxicity as a rare differential diagnosis to hypoxic ischaemic encephalopathy.

A term newborn girl presented with apnoea and seizures at approximately 20 min of life following an uneventful vaginal delivery. She required admission to the Neonatal Intensive Care Unit following intubation and was commenced on conventional ventilation. Her mother had received a local lidocaine injection for an episiotomy prior to delivery. Initial investigations confirmed electrographic seizures for which she received an anticonvulsant with successful termination of seizure activity. Investigations for hypoxic injury, intracranial trauma, structural brain abnormalities, metabolic disorders and infection were unremarkable. Her blood lidocaine level was subsequently found to be elevated, confirming lidocaine toxicity as the cause of presentation. She demonstrated clinical improvement with no evidence of complications at time of discharge or on early follow-up.

Improving Cohort-Hospital Matching Accuracy through Standardization and Validation of Participant Identifiable Information.

Linking very large, consented birth cohorts to birthing hospitals clinical data could elucidate the lifecourse outcomes of health care and exposures during the pregnancy, birth and newborn periods. Unfortunately, cohort personally identifiable information (PII) often does not include unique identifier numbers, presenting matching challenges. To develop optimized cohort matching to birthing hospital clinical records, this pilot drew on a one-year (December 2020-December 2021) cohort for a single Australian birthing hospital participating in the whole-of-state Generation Victoria (GenV) study. For 1819 consented mother-baby pairs and 58 additional babies (whose mothers were not themselves participating), we tested the accuracy and effort of various approaches to matching. We selected demographic variables drawn from names, DOB, sex, telephone, address (and birth order for multiple births). After variable standardization and validation, accuracy rose from 10% to 99% using a deterministic-rule-based approach in 10 steps. Using cohort-specific modifications of the Australian Statistical Linkage Key (SLK-581), it took only 3 steps to reach 97% (SLK-5881) and 98% (SLK-5881.1) accuracy. We conclude that our SLK-5881 process could safely and efficiently achieve high accuracy at the population level for future birth cohort-birth hospital matching in the absence of unique identifier numbers.

Comparing the effect of different loading doses of phenobarbitone on serum phenobarbitone levels in babies with neonatal seizures and effect of therapeutic hypothermia on phenobarbitone levels.

BACKGROUND: With current recommendation for phenobarbitone dosing, we have noted that babies are extremely sedated with elevated serum phenobarbitone levels. We postulate that asphyxiated neonates with hypoxic liver injury have impaired drug metabolism and renal injury affects drug elimination, thus elevating serum drug levels. Therapeutic hypothermia (TH) could further affect the drug levels. OBJECTIVE: To determine the serum levels of the phenobarbitone in babies receiving different loading doses of phenobarbitone for neonatal seizures and to study the effect of asphyxia and TH on drug levels. DESIGN: Prospective observational cohort study. MATERIAL AND METHODS: Term neonates with seizures of any cause were given phenobarbitone up to a maximum loading of 40 mg/kg followed by maintenance dose of 5 mg/kg/day. Serum phenobarbitone levels were assessed after 4 h of the initial loading dose and subsequently at 24, 48 and 72 h from the time after maximum loading dose. Babies were divided into three groups Group 1 (HIE + TH-hypoxic ischemic encephalopathy undergoing TH), Group 2 (HIE - TH-hypoxic ischemic encephalopathy without TH) and Group 3 (non-HIE group). RESULTS: A total of 47 babies completed the study. Twenty-three (49%) received 20 mg/kg, 14 (30%) received 30 mg/kg and 10 (21%) received 40 mg per kg of phenobarbitone as loading dose. HIE was the major cause of seizures 28 (59%) followed by hypoglycemia 7 (14%), cerebral malformations 4 (8%), inborn errors of metabolism 2 (4%) and hypocalcemia 1 (2%) while the cause of seizures was not known in 6 (13%). Median (IQR) Phenobarbitone levels at 72 h in babies who received 20 mg/kg loading dose of phenobarbitone was 46.72 (44.02-50.49) mcg/ml in HIE + TH group, 40.53 (28.66-65.09) mcg/ml in HIE - TH group and 49 (37-65) mcg/ml in non-HIE group. After a loading dose of 30 mg/kg, phenobarbitone level was 63.76 (59.5-65.94) mcg/ml in HIE + TH group, 42.5 (34.75-48.75) mcg/ml in HIE - TH group and 42.07 (40-49.05) mcg/ml in non-HIE group. After 40 mg/kg loading dose, it was 62.3 (60.2-64.9) mcg/ml in HIE + TH group, 57.0 (49.8-60.2) mcg/ml in HIE - TH group and 48.15 (40.8-50.97) mcg/ml in non-HIE group. In babies who received >20 mg/kg loading dose, 100% of HIE + TH, 80% of HIE - TH and 60% of non-HIE had supratherapeutic levels of phenobarbitone. CONCLUSION: At higher loading doses of 30 and 40 mg/kg, steady state concentration of serum phenobarbitone is higher in babies with hypoxic ischemic encephalopathy who underwent TH than in babies with non-HIE causes of seizures. Loading dose beyond 20 mg/kg should be used with close monitoring of serum drug level.

Seizures are common in new born period and the most common cause of seizures is due to impaired blood and oxygen supply to brain. Phenobarbitone is the drug of choice for new born seizures. With the current recommended dosage for phenobarbitone (40 mg/kg), we have noticed that babies are drowsier and their blood levels of phenobarbitone are more than the normal expected range. The reason for these observations may be due to impaired processing of drug by the body due to decreased oxygen supply to liver and kidney. Whole body cooling which is a proven treatment intervention for babies with asphyxia can also alter drug metabolism. We conducted a study to assess the effect of whole-body cooling and hypoxia on the serum phenobarbitone levels. Babies who received phenobarbitone for seizures were divided into three groups. Group 1, seizures due to hypoxia who underwent whole body cooling, Group 2, seizures due to hypoxia but no whole body cooling and Group 3, seizures due to causes other than hypoxia. We found that 100% babies in Group 1 and 80% in Group 2 and 60% in Group 3 had higher levels of phenobarbitone in blood at more than 20 mg/kg loading dose.

Novel Mutations in CRLF1: Case Reports with Crisponi Syndrome.

Crisponi syndrome (CS) is a rare autosomal recessive syndrome, characterized by episodic facial muscle contraction with trismus, abundant salivation along with intermittent hyperthermia, feeding difficulties, characteristic facial dysmorphism, and camptodactyly. Here the authors report two South Indian neonates with confirmed diagnosis of Crisponi syndrome, caused by novel pathogenic variants in cytokine receptor-like factor 1 (CRLF1) gene. The classical clinical findings observed in the present cases were feeding difficulty, facial dysmorphism, tachypnea, contractures, camptodactyly, opisthotonus, hyperthermia, poor growth, and facial muscle contraction resembling probable tetanus. The patients with variants identified in the signal peptide domain had typical spasms from day one of life as compared to the variants in other domains who had later onset at neonatal period. The authors provide a review of the cases described, so far, from India highlighting that no common variants attribute to this rare syndrome. Recognizing this syndrome is crucial to differentiate it from infective conditions and for effective genetic counseling. Though tetanus is almost eradicated in developing countries, genetic causes should be suspected in new cases.

Development and Validation of a Deep Learning Method to Predict Cerebral Palsy From Spontaneous Movements in Infants at High Risk.

Importance: Early identification of cerebral palsy (CP) is important for early intervention, yet expert-based assessments do not permit widespread use, and conventional machine learning alternatives lack validity. Objective: To develop and assess the external validity of a novel deep learning-based method to predict CP based on videos of infants' spontaneous movements at 9 to 18 weeks' corrected age. Design, Setting, and Participants: This prognostic study of a deep learning-based method to predict CP at a corrected age of 12 to 89 months involved 557 infants with a high risk of perinatal brain injury who were enrolled in previous studies conducted at 13 hospitals in Belgium, India, Norway, and the US between September 10, 2001, and October 25, 2018. Analysis was performed between February 11, 2020, and September 23, 2021. Included infants had available video recorded during the fidgety movement period from 9 to 18 weeks' corrected age, available classifications of fidgety movements ascertained by the general movement assessment (GMA) tool, and available data on CP status at 12 months' corrected age or older. A total of 418 infants (75.0%) were randomly assigned to the model development (training and internal validation) sample, and 139 (25.0%) were randomly assigned to the external validation sample (1 test set). Exposure: Video recording of spontaneous movements. Main Outcomes and Measures: The primary outcome was prediction of CP. Deep learning-based prediction of CP was performed automatically from a single video. Secondary outcomes included prediction of associated functional level and CP subtype. Sensitivity, specificity, positive and negative predictive values, and accuracy were assessed. Results: Among 557 infants (310 [55.7%] male), the median (IQR) corrected age was 12 (11-13) weeks at assessment, and 84 infants (15.1%) were diagnosed with CP at a mean (SD) age of 3.4 (1.7) years. Data on race and ethnicity were not reported because previous studies (from which the infant samples were derived) used different study protocols with inconsistent collection of these data. On external validation, the deep learning-based CP prediction method had sensitivity of 71.4% (95% CI, 47.8%-88.7%), specificity of 94.1% (95% CI, 88.2%-97.6%), positive predictive value of 68.2% (95% CI, 45.1%-86.1%), and negative predictive value of 94.9% (95% CI, 89.2%-98.1%). In comparison, the GMA tool had sensitivity of 70.0% (95% CI, 45.7%-88.1%), specificity of 88.7% (95% CI, 81.5%-93.8%), positive predictive value of 51.9% (95% CI, 32.0%-71.3%), and negative predictive value of 94.4% (95% CI, 88.3%-97.9%). The deep learning method achieved higher accuracy than the conventional machine learning method (90.6% [95% CI, 84.5%-94.9%] vs 72.7% [95% CI, 64.5%-79.9%]; P < .001), but no significant improvement in accuracy was observed compared with the GMA tool (85.9%; 95% CI, 78.9%-91.3%; P = .11). The deep learning prediction model had higher sensitivity among infants with nonambulatory CP (100%; 95% CI, 63.1%-100%) vs ambulatory CP (58.3%; 95% CI, 27.7%-84.8%; P = .02) and spastic bilateral CP (92.3%; 95% CI, 64.0%-99.8%) vs spastic unilateral CP (42.9%; 95% CI, 9.9%-81.6%; P < .001). Conclusions and Relevance: In this prognostic study, a deep learning-based method for predicting CP at 9 to 18 weeks' corrected age had predictive accuracy on external validation, which suggests possible avenues for using deep learning-based software to provide objective early detection of CP in clinical settings.

Prediction of outcome from MRI and general movements assessment after hypoxic-ischaemic encephalopathy in low-income and middle-income countries: data from a randomised controlled trial.

OBJECTIVE: To evaluate the accuracy of neonatal MRI and general movements assessment (GMA) in predicting neurodevelopmental outcomes in infants with hypoxic-ischaemic encephalopathy (HIE). DESIGN: Secondary analyses of a randomised controlled trial (RCT). SETTING: Tertiary neonatal intensive care unit in India. METHODS: Fifty infants with HIE were included in an RCT of therapeutic hypothermia (25 cooled and 25 non-cooled). All infants underwent brain MRI at day 5, GMA at 10-15 weeks and outcome assessments including Bayley Scales of Infant and Toddler Development, third edition, at 18 months. Associations between patterns of brain injury, presence/absence of fidgety movements (FMs) and outcomes were assessed. RESULTS: Seventeen of 47 (36%) had adverse outcome (5 (21%) cooled vs 12 (52%) non-cooled, p=0.025). Eight infants died (four before an MRI, another three before GMA). Two developed severe cerebral palsy and seven had Bayley-III motor/cognitive composite score <85. Twelve (26%) had moderately/severely abnormal MRI and nine (23%) had absent FMs. The positive predictive value (95% CI) of an adverse outcome was 89% (53% to 98%) for moderate/severe basal ganglia and thalami (BGT) injury, 83% (56% to 95%) for absent/equivocal signal in the posterior limb of the internal capsule (PLIC) and 67% (38% to 87%) for absent FMs. Negative predictive values (95% CI) were 85% (74% to 92%) for normal/mild BGT injury, 90% (78% to 96%) for normal PLIC and 86% (74% to 93%) for present FMs. CONCLUSIONS: Neonatal MRI and GMA predicted outcomes with high accuracy in infants with HIE. The GMA is a feasible low-cost method which can be used alone or complementary to MRI in low-resource settings to prognosticate and direct follow-up. TRIAL REGISTRATION NUMBER: CTRI/2013/05/003693.

Placental chorioangioma: an unusual cause of neonatal cardiomyopathy.

A late preterm baby presented with clinical and echocardiographic features of cardiomyopathy and cardiac failure soon after birth. After extensive metabolic, infective and genetic investigations, the likely cause was established to be due to multiple small placental chorioangiomas. While large placental chorioangiomas are associated with maternal, fetal and neonatal complications, small chorioangiomas are usually asymptomatic and diagnosed incidentally on placental histology. Our case demonstrates that multiple small chorioangiomas might behave like a giant chorioangioma, causing significant neonatal morbidity. This report also highlights the importance of assessing the placental histology where no identifiable cause for neonatal cardiomyopathy can be found.

High versus standard volume enteral feeds to promote growth in preterm or low birth weight infants.

BACKGROUND: Human milk is the best enteral nutrition for preterm infants. However, human milk, given at standard recommended volumes, is not adequate to meet the protein, energy, and other nutrient requirements of preterm or low birth weight infants. One strategy that may be used to address the potential nutrient deficits is to give a higher volume of enteral feeds. High volume feeds may improve nutrient accretion and growth, and in turn may improve neurodevelopmental outcomes. However, there are concerns that high volume feeds may cause feed intolerance, necrotising enterocolitis, or complications related to fluid overload such as patent ductus arteriosus and chronic lung disease. This is an update of a review published in 2017. OBJECTIVES: To assess the effect on growth and safety of high versus standard volume enteral feeds in preterm or low birth weight infants. In infants who were fed fortified human milk or preterm formula, high and standard volume feeds were defined as > 180 mL/kg/day and ≤ 180 mL/kg/day, respectively. In infants who were fed unfortified human milk or term formula, high and standard volume feeds were defined as > 200 mL/kg/day and ≤ 200 mL/kg/day, respectively. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020 Issue 6) in the Cochrane Library; Ovid MEDLINE (1946 to June 2020); Embase (1974 to June 2020); and CINAHL (inception to June 2020); Maternity & Infant Care Database (MIDIRS) (1971 to April 2020); as well as previous reviews, and trial registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared high versus standard volume enteral feeds for preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported risk ratio (RR) and risk difference for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence. The primary outcomes were weight gain, linear and head growth during hospital stay, and extrauterine growth restriction at discharge. MAIN RESULTS: We included two new RCTs (283 infants) in this update. In total, we included three trials (347 infants) in this updated review. High versus standard volume feeds with fortified human milk or preterm formula Two trials (283 infants) met the inclusion criteria for this comparison. Both were of good methodological quality, except for lack of masking. Both trials were performed in infants born at < 32 weeks' gestation. Meta-analysis of data from both trials showed high volume feeds probably improves weight gain during hospital stay (MD 2.58 g/kg/day, 95% CI 1.41 to 3.76; participants = 271; moderate-certainty evidence). High volume feeds may have little or no effect on linear growth (MD 0.05 cm/week, 95% CI -0.02 to 0.13; participants = 271; low-certainty evidence), head growth (MD 0.02 cm/week, 95% CI -0.04 to 0.09; participants = 271; low-certainty evidence), and extrauterine growth restriction at discharge (RR 0.71, 95% CI 0.50 to 1.02; participants = 271; low-certainty evidence). We are uncertain of the effect of high volume feeds with fortified human milk or preterm formula on the risk of necrotising enterocolitis (RR 0.74, 95% CI 0.12 to 4.51; participants = 283; very-low certainty evidence). High versus standard volume feeds with unfortified human milk or term formula One trial with 64 very low birth weight infants met the inclusion criteria for this comparison. This trial was unmasked but otherwise of good methodological quality. High volume feeds probably improves weight gain during hospital stay (MD 6.2 g/kg/day, 95% CI 2.71 to 9.69; participants = 61; moderate-certainty evidence). The trial did not provide data on linear and head growth, and extrauterine growth restriction at discharge. We are uncertain as to the effect of high volume feeds with unfortified human milk or term formula on the risk of necrotising enterocolitis (RR 1.03, 95% CI 0.07 to 15.78; participants = 61; very low-certainty evidence). AUTHORS' CONCLUSIONS: High volume feeds (≥ 180 mL/kg/day of fortified human milk or preterm formula, or ≥ 200 mL/kg/day of unfortified human milk or term formula) probably improves weight gain during hospital stay. The available data is inadequate to draw conclusions on the effect of high volume feeds on other growth and clinical outcomes. A large RCT is needed to provide data of sufficient quality and precision to inform policy and practice.