Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome.

BACKGROUND: Laryngeal mask airway surfactant administration (S-LMA) has the potential benefit of surfactant administration whilst avoiding endotracheal intubation and ventilation, ventilator-induced lung injury and bronchopulmonary dysplasia (BPD). OBJECTIVES: To evaluate the benefits and harms of S-LMA either as prophylaxis or treatment (rescue) compared to placebo, no treatment, or intratracheal surfactant administration via an endotracheal tube (ETT) with the intent to rapidly extubate (InSurE) or extubate at standard criteria (S-ETT) or via other less-invasive surfactant administration (LISA) methods on morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome (RDS). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trial registries in December 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster- or quasi-RCTs of S-LMA compared to placebo, no treatment, or other routes of administration (nebulised, pharyngeal instillation of surfactant before the first breath, thin endotracheal catheter surfactant administration or intratracheal surfactant instillation) on morbidity and mortality in preterm infants at risk of RDS. We considered published, unpublished and ongoing trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included eight trials (seven new to this update) recruiting 510 newborns. Five trials (333 infants) compared S-LMA with surfactant administration via ETT with InSurE. One trial (48 infants) compared S-LMA with surfactant administration via ETT with S-ETT, and two trials (129 infants) compared S-LMA with no surfactant administration. We found no studies comparing S-LMA with LISA techniques or prophylactic or early S-LMA. S-LMA versus surfactant administration via InSurE S-LMA may have little or no effect on the composite outcome of death or BPD at 36 weeks' postmenstrual age (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.27 to 8.34, I 2 = not applicable (NA) as 1 study had 0 events; risk difference (RD) 0.02, 95% CI -0.07 to 0.10; I 2 = 0%; 2 studies, 110 infants; low-certainty evidence). There may be a reduction in the need for mechanical ventilation at any time (RR 0.53, 95% CI 0.36 to 0.78; I 2 = 27%; RD -0.14, 95% CI -0.22 to -0.06, I 2 = 89%; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 5 to 17; 5 studies, 333 infants; low-certainty evidence). However, this was limited to four studies (236 infants) using analgesia or sedation for the InSurE group. There was little or no difference for air leak during first hospitalisation (RR 1.39, 95% CI 0.65 to 2.98; I 2 = 0%; 5 studies, 333 infants (based on 3 studies as 2 studies had 0 events); low-certainty evidence); BPD among survivors to 36 weeks' PMA (RR 1.28, 95% CI 0.47 to 3.52; I 2 = 0%; 4 studies, 264 infants (based on 3 studies as 1 study had 0 events); low-certainty evidence); or death (all causes) during the first hospitalisation (RR 0.28, 95% CI 0.01 to 6.60; I 2 = NA as 2 studies had 0 events; 3 studies, 203 infants; low-certainty evidence). Neurosensory disability was not reported. Intraventricular haemorrhage ( IVH) grades III and IV were reported among the study groups (1 study, 50 infants). S-LMA versus surfactant administration via S-ETT No study reported death or BPD at 36 weeks' PMA. S-LMA may reduce the use of mechanical ventilation at any time compared with S-ETT (RR 0.47, 95% CI 0.31 to 0.71; RD -0.54, 95% CI -0.74 to -0.34; NNTB 2, 95% CI 2 to 3; 1 study, 48 infants; low-certainty evidence). We are very uncertain whether S-LMA compared with S-ETT reduces air leak during first hospitalisation (RR 2.56, 95% CI 0.11 to 59.75), IVH grade III or IV (RR 2.56, 95% CI 0.11 to 59.75) and death (all causes) during the first hospitalisation (RR 0.17, 95% CI 0.01 to 3.37) (1 study, 48 infants; very low-certainty evidence). No study reported BPD to 36 weeks' PMA or neurosensory disability. S-LMA versus no surfactant administration Rescue surfactant could be used in both groups. There may be little or no difference in death or BPD at 36 weeks (RR 1.65, 95% CI 0.85 to 3.22; I 2 = 58%; RD 0.08, 95% CI -0.03 to 0.19; I 2 = 0%; 2 studies, 129 infants; low-certainty evidence). There was probably a reduction in the need for mechanical ventilation at any time with S-LMA compared with nasal continuous positive airway pressure without surfactant (RR 0.57, 95% CI 0.38 to 0.85; I 2 = 0%; RD -0.24, 95% CI -0.40 to -0.08; I 2 = 0%; NNTB 4, 95% CI 3 to 13; 2 studies, 129 infants; moderate-certainty evidence). There was little or no difference in air leak during first hospitalisation (RR 0.65, 95% CI 0.23 to 1.88; I 2 = 0%; 2 studies, 129 infants; low-certainty evidence) or BPD to 36 weeks' PMA (RR 1.65, 95% CI 0.85 to 3.22; I 2 = 58%; 2 studies, 129 infants; low-certainty evidence). There were no events in either group for death during the first hospitalisation (1 study, 103 infants) or IVH grade III and IV (1 study, 103 infants). No study reported neurosensory disability. AUTHORS' CONCLUSIONS: In preterm infants less than 36 weeks' PMA, rescue S-LMA may have little or no effect on the composite outcome of death or BPD at 36 weeks' PMA. However, it may reduce the need for mechanical ventilation at any time. This benefit is limited to trials reporting the use of analgesia or sedation in the InSurE and S-ETT groups. There is low- to very-low certainty evidence for no or little difference in neonatal morbidities and mortality. Long-term outcomes are largely unreported. In preterm infants less than 32 weeks' PMA or less than 1500 g, there are insufficient data to support or refute the use of S-LMA in clinical practice. Adequately powered trials are required to determine the effect of S-LMA for prevention or early treatment of RDS in extremely preterm infants. S-LMA use should be limited to clinical trials in this group of infants.

Population Dynamics of a Declining White-Tailed Deer Population in the Southern Appalachian Region of the United States.

Although generally abundant, white-tailed deer (Odocoileus virginianus) populations in the southeastern United States have recently experienced several localized declines attributed to reduced fawn recruitment following the establishment of coyotes (Canis latrans). The Southern Appalachians is a mountainous region suggested to be experiencing white-tailed deer declines, as harvest numbers and hunter success rates have substantially decreased in northern Georgia since 1979. Low fawn survival (16%) was also recently documented in the Chattahoochee National Forest (CNF) in northern Georgia, necessitating further examination. We radio-collared 14 yearling and 45 adult female white-tailed deer along with 71 fawns during 2018-2020 in the CNF to estimate field-based vital rates (i.e., survival and fecundity) and parameterize stage-structured population models. We projected population growth rates (λ) over 10 years to evaluate the current rate of decline and various other management scenarios. Our results indicated that the observed population would decline by an average of 4.0% annually (λ = 0.960) under current conditions. Only scenarios including antlerless harvest restrictions in addition to improved fawn survival resulted in positive growth (λ = 1.019, 1.085), suggesting these measures are likely necessary for population recovery in the region. This approach can be applied by wildlife managers to inform site-specific management strategies.

Higher versus lower sodium intake for preterm infants.

BACKGROUND: Infants born preterm are at increased risk of early hypernatraemia (above-normal blood sodium levels) and late hyponatraemia (below-normal blood sodium levels). There are concerns that imbalances of sodium intake may impact neonatal morbidities, growth and developmental outcomes. OBJECTIVES: To determine the effects of higher versus lower sodium supplementation in preterm infants. SEARCH METHODS: We searched CENTRAL in February 2023; and MEDLINE, Embase and trials registries in March and April 2022. We checked reference lists of included studies and systematic reviews where subject matter related to the intervention or population examined in this review. We compared early (< 7 days following birth), late (≥ 7 days following birth), and early and late sodium supplementation, separately. SELECTION CRITERIA: We included randomised, quasi-randomised or cluster-randomised controlled trials that compared nutritional supplementation that included higher versus lower sodium supplementation in parenteral or enteral intake, or both. Eligible participants were preterm infants born before 37 weeks' gestational age or with a birth weight less than 2500 grams, or both. We excluded studies that had prespecified differential water intakes between groups. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and risk of bias, and extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included nine studies in total. However, we were unable to extract data from one study (20 infants); some studies contributed to more than one comparison. Eight studies (241 infants) were available for quantitative meta-analysis. Four studies (103 infants) compared early higher versus lower sodium intake, and four studies (138 infants) compared late higher versus lower sodium intake. Two studies (103 infants) compared intermediate sodium supplementation (≥ 3 mmol/kg/day to < 5 mmol/kg/day) versus no supplementation, and two studies (52 infants) compared higher sodium supplementation (≥ 5 mmol/kg/day) versus no supplementation. We assessed only two studies (63 infants) as low risk of bias. Early (less than seven days following birth) higher versus lower sodium intake Early higher versus lower sodium intake may not affect mortality (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.38 to 2.72; I2 = 0%; 3 studies, 83 infants; low-certainty evidence). Neurodevelopmental follow-up was not reported. Early higher versus lower sodium intake may lead to a similar incidence of hyponatraemia < 130 mmol/L (RR 0.68, 95% CI 0.40 to 1.13; I2 = 0%; 3 studies, 83 infants; low-certainty evidence) but an increased incidence of hypernatraemia ≥ 150 mmol/L (RR 1.62, 95% CI 1.00 to 2.65; I2 = 0%; 4 studies, 103 infants; risk difference (RD) 0.17, 95% CI 0.01 to 0.34; number needed to treat for an additional harmful outcome 6, 95% CI 3 to 100; low-certainty evidence). Postnatal growth failure was not reported. The evidence is uncertain for an effect on necrotising enterocolitis (RR 4.60, 95% CI 0.23 to 90.84; 1 study, 46 infants; very low-certainty evidence). Chronic lung disease at 36 weeks was not reported. Late (seven days or more following birth) higher versus lower sodium intake Late higher versus lower sodium intake may not affect mortality (RR 0.13, 95% CI 0.01 to 2.20; 1 study, 49 infants; very low-certainty evidence). Neurodevelopmental follow-up was not reported. Late higher versus lower sodium intake may reduce the incidence of hyponatraemia < 130 mmol/L (RR 0.13, 95% CI 0.03 to 0.50; I2 = 0%; 2 studies, 69 infants; RD -0.42, 95% CI -0.59 to -0.24; number needed to treat for an additional beneficial outcome 2, 95% CI 2 to 4; low-certainty evidence). The evidence is uncertain for an effect on hypernatraemia ≥ 150 mmol/L (RR 7.88, 95% CI 0.43 to 144.81; I2 = 0%; 2 studies, 69 infants; very low-certainty evidence). A single small study reported that later higher versus lower sodium intake may reduce the incidence of postnatal growth failure (RR 0.25, 95% CI 0.09 to 0.69; 1 study; 29 infants; low-certainty evidence). The evidence is uncertain for an effect on necrotising enterocolitis (RR 0.07, 95% CI 0.00 to 1.25; 1 study, 49 infants; very low-certainty evidence) and chronic lung disease (RR 2.03, 95% CI 0.80 to 5.20; 1 study, 49 infants; very low-certainty evidence). Early and late (day 1 to 28 after birth) higher versus lower sodium intake for preterm infants Early and late higher versus lower sodium intake may not have an effect on hypernatraemia ≥ 150 mmol/L (RR 2.50, 95% CI 0.63 to 10.00; 1 study, 20 infants; very low-certainty evidence). No other outcomes were reported. AUTHORS' CONCLUSIONS: Early (< 7 days following birth) higher sodium supplementation may result in an increased incidence of hypernatraemia and may result in a similar incidence of hyponatraemia compared to lower supplementation. We are uncertain if there are any effects on mortality or neonatal morbidity. Growth and longer-term development outcomes were largely unreported in trials of early sodium supplementation. Late (≥ 7 days following birth) higher sodium supplementation may reduce the incidence of hyponatraemia. We are uncertain if late higher intake affects the incidence of hypernatraemia compared to lower supplementation. Late higher sodium intake may reduce postnatal growth failure. We are uncertain if late higher sodium intake affects mortality, other neonatal morbidities or longer-term development. We are uncertain if early and late higher versus lower sodium supplementation affects outcomes.

White-tailed deer (Odocoileus virginianus) fawn survival and the influence of landscape characteristics on fawn predation risk in the Southern Appalachian Mountains, USA.

In the Southern Appalachian region of the United States, harvest data has indicated the occurrence of low deer densities while exposing a trend of declining white-tailed deer (Odocoileus virginianus) populations over the past several decades in northern Georgia. A triumvirate of increasing fawn predator populations reside in the Southern Appalachian Mountains including coyotes (Canis latrans), black bears (Ursus americanus) and bobcats (Lynx rufus). This region is also characterized by a homogenous landscape composed of mature forests and sparse understory vegetation, likely lacking adequate cover to offer fawns refugia from predators. Our objectives were to estimate survival and cause-specific mortality rates of fawns while assessing a possible link between mortality risk, intrinsic fawn characteristics (i.e., birth mass, Julian birth date, sibling status), and landscape features within fawn usage areas. During 2018-2020, we radio-collared 71 fawns within the Chattahoochee National Forest of northern Georgia, USA and monitored survival to 12 weeks of age. We observed low fawn survival (cumulative = 0.157, 95% CI = 0.091-0.273; vaginal implant transmitter = 0.196, 95% CI = 0.096-0.403) with predation as the leading cause of all known mortalities (45 of 55 mortalities; 82%) due primarily to coyotes (n = 22), black bears (n = 12), and bobcats (n = 7). Relationships between landscape features and fawn predation risk were minimal with only one informative covariate. Increasing amounts of early successional land cover within fawn usage areas decreased fawn mortality risk within the first 20 days of life, but elevated mortality risk thereafter. All fawns with any amount of early successional land cover in their usage areas died of predation (n = 13) at various time intervals, suggesting limited areas of potential fawning cover may be targeted by predators. However, fawn predation risk seemed to be high regardless of landscape covariates due to the limited number of surviving fawns. Coyote-caused mortality occurred over a longer period at a consistently higher magnitude than all other forms of mortality, indicating possible delayed prey-switching behavior and coyote predation as an important factor of fawn survival. The low recruitment of fawns influenced by high predation rates and homogenous habitat conditions is likely the cause of deer population declines in the region.

Effect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial.

Importance: Seizures in the neonatal period are associated with increased mortality and morbidity. Bedside amplitude-integrated electroencephalography (aEEG) has facilitated the detection of electrographic seizures; however, whether these seizures should be treated remains uncertain. Objective: To determine if the active management of electrographic and clinical seizures in encephalopathic term or near-term neonates improves survival free of severe disability at 2 years of age compared with only treating clinically detected seizures. Design, Setting, and Participants: This randomized clinical trial was conducted in tertiary newborn intensive care units recruited from 2012 to 2016 and followed up until 2 years of age. Participants included neonates with encephalopathy at 35 weeks' gestation or more and younger than 48 hours old. Data analysis was completed in April 2021. Interventions: Randomization was to an electrographic seizure group (ESG) in which seizures detected on aEEG were treated in addition to clinical seizures or a clinical seizure group (CSG) in which only seizures detected clinically were treated. Main Outcomes and Measures: Primary outcome was death or severe disability at 2 years, defined as scores in any developmental domain more than 2 SD below the Australian mean assessed with Bayley Scales of Neonate and Toddler Development, 3rd ed (BSID-III), or the presence of cerebral palsy, blindness, or deafness. Secondary outcomes included magnetic resonance imaging brain injury score at 5 to 14 days, time to full suck feeds, and individual domain scores on BSID-III at 2 years. Results: Of 212 randomized neonates, the mean (SD) gestational age was 39.2 (1.7) weeks and 122 (58%) were male; 152 (72%) had moderate to severe hypoxic-ischemic encephalopathy (HIE) and 147 (84%) had electrographic seizures. A total of 86 neonates were included in the ESG group and 86 were included in the CSG group. Ten of 86 (9%) neonates in the ESG and 4 of 86 (4%) in the CSG died before the 2-year assessment. The odds of the primary outcome were not significantly different in the ESG group compared with the CSG group (ESG, 38 of 86 [44%] vs CSG, 27 of 86 [31%]; odds ratio [OR], 1.83; 95% CI, 0.96 to 3.49; P = .14). There was also no significant difference in those with HIE (OR, 1.77; 95% CI, 0.84 to 3.73; P = .26). There was evidence that cognitive outcomes were worse in the ESG (mean [SD] scores, ESG: 97.4 [17.7] vs CSG: 103.8 [17.3]; mean difference, -6.5 [95% CI, -1.2 to -11.8]; P = .01). There was little evidence of a difference in secondary outcomes, including time to suck feeds, seizure burden, or brain injury score. Conclusions and Relevance: Treating electrographic and clinical seizures with currently used anticonvulsants did not significantly reduce the rate of death or disability at 2 years in a heterogeneous group of neonates with seizures. Trial Registration: http://anzctr.org.au Identifier: ACTRN12611000327987.

Opioid treatment for opioid withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using an opioid for treatment of NAS due to withdrawal from opioids in newborn infants. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via Cochrane Register of Studies Web and MEDLINE via Ovid. We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for eligible trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi- and cluster-RCTs which enrolled infants born to mothers with opioid dependence and who were experiencing NAS requiring treatment with an opioid. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 16 trials (1110 infants) with NAS secondary to maternal opioid use in pregnancy. Seven studies at low risk of bias were included in sensitivity analysis. Opioid versus no treatment / usual care: a single trial (80 infants) of morphine and supportive care versus supportive care alone reported no difference in treatment failure (risk ratio (RR) 1.29, 95% confidence interval (CI) 0.41 to 4.07; very low certainty evidence). No infant had a seizure. The trial did not report mortality, neurodevelopmental disability and adverse events. Morphine increased days hospitalisation (mean difference (MD) 15.00, 95% CI 8.86 to 21.14; very low certainty evidence) and treatment (MD 12.50, 95% CI 7.52 to 17.48; very low certainty evidence), but decreased days to regain birthweight (MD -2.80, 95% CI -5.33 to -0.27) and duration (minutes) of supportive care each day (MD -197.20, 95% CI -274.15 to -120.25). Morphine versus methadone: there was no difference in treatment failure (RR 1.59, 95% CI 0.95 to 2.67; 2 studies, 147 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study reported no difference in days hospitalisation (MD 1.40, 95% CI -3.08 to 5.88; 116 infants; low certainty evidence), whereas data from two studies found an increase in days treatment (MD 2.71, 95% CI 0.22 to 5.21; 147 infants; low certainty) for infants treated with morphine. A single study reported no difference in breastfeeding, adverse events, or out of home placement. Morphine versus sublingual buprenorphine: there was no difference in treatment failure (RR 0.79, 95% CI 0.36 to 1.74; 3 studies, 113 infants; very low certainty evidence). Neonatal or infant mortality and neurodevelopmental disability were not reported. There was moderate certainty evidence of an increase in days hospitalisation (MD 11.45, 95% CI 5.89 to 17.01; 3 studies, 113 infants), and days treatment (MD 12.79, 95% CI 7.57 to 18.00; 3 studies, 112 infants) for infants treated with morphine. A single adverse event (seizure) was reported in infants exposed to buprenorphine. Morphine versus diluted tincture of opium (DTO): a single study (33 infants) reported no difference in days hospitalisation, days treatment or weight gain (low certainty evidence). Opioid versus clonidine: a single study (31 infants) reported no infant with treatment failure in either group. This study did not report seizures, neonatal or infant mortality and neurodevelopmental disability. There was low certainty evidence for no difference in days hospitalisation or days treatment. This study did not report adverse events. Opioid versus diazepam: there was a reduction in treatment failure from use of an opioid (RR 0.43, 95% CI 0.23 to 0.80; 2 studies, 86 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study of 34 infants comparing methadone versus diazepam reported no difference in days hospitalisation or days treatment (very low certainty evidence). Adverse events were not reported. Opioid versus phenobarbital: there was a reduction in treatment failure from use of an opioid (RR 0.51, 95% CI 0.35 to 0.74; 6 studies, 458 infants; moderate certainty evidence). Subgroup analysis found a reduction in treatment failure in trials titrating morphine to ≧ 0.5 mg/kg/day (RR 0.21, 95% CI 0.10 to 0.45; 3 studies, 230 infants), whereas a single study using morphine < 0.5 mg/kg/day reported no difference compared to use of phenobarbital (subgroup difference P = 0.05). Neonatal or infant mortality and neurodevelopmental disability were not reported. A single study (111 infants) of paregoric versus phenobarbital reported seven infants with seizures in the phenobarbital group, whereas no seizures were reported in two studies (170 infants) comparing morphine to phenobarbital. There was no difference in days hospitalisation or days treatment. A single study (96 infants) reported no adverse events in either group. Opioid versus chlorpromazine: there was a reduction in treatment failure from use of morphine versus chlorpromazine (RR 0.08, 95% CI 0.01 to 0.62; 1 study, 90 infants; moderate certainty evidence). No seizures were reported in either group. There was low certainty evidence for no difference in days treatment. This trial reported no adverse events in either group. None of the included studies reported time to control of NAS. Data for duration and severity of NAS were limited, and we were unable to use these data in quantitative synthesis. AUTHORS' CONCLUSIONS: Compared to supportive care alone, the addition of an opioid may increase duration of hospitalisation and treatment, but may reduce days to regain birthweight and the duration of supportive care each day. Use of an opioid may reduce treatment failure compared to phenobarbital, diazepam or chlorpromazine. Use of an opioid may have little or no effect on duration of hospitalisation or treatment compared to use of phenobarbital, diazepam or chlorpromazine. The type of opioid used may have little or no effect on the treatment failure rate. Use of buprenorphine probably reduces duration of hospitalisation and treatment compared to morphine, but there are no data for time to control NAS with buprenorphine, and insufficient evidence to determine safety. There is insufficient evidence to determine the effectiveness and safety of clonidine.

Sedatives for opioid withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using a sedative versus control (placebo, usual treatment or non-pharmacological treatment) for NAS due to withdrawal from opioids and determine which type of sedative is most effective and safe for NAS due to withdrawal from opioids. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included trials enrolling infants with NAS born to mothers with an opioid dependence with more than 80% follow-up and using randomised, quasi-randomised and cluster-randomised allocation to sedative or control. DATA COLLECTION AND ANALYSIS: Three review authors assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 10 trials (581 infants) with NAS secondary to maternal opioid use in pregnancy. There were multiple comparisons of different sedatives and regimens. There were limited data available for use in sensitivity analysis of studies at low risk of bias. Phenobarbital versus supportive care: one study reported there may be little or no difference in treatment failure with phenobarbital and supportive care versus supportive care alone (risk ratio (RR) 2.73, 95% confidence interval (CI) 0.94 to 7.94; 62 participants; very low-certainty evidence). No infant had a clinical seizure. The study did not report mortality, neurodevelopmental disability and adverse events. There may be an increase in days' hospitalisation and treatment from use of phenobarbital (hospitalisation: mean difference (MD) 20.80, 95% CI 13.64 to 27.96; treatment: MD 17.90, 95% CI 11.98 to 23.82; both 62 participants; very low-certainty evidence). Phenobarbital versus diazepam: there may be a reduction in treatment failure with phenobarbital versus diazepam (RR 0.39, 95% CI 0.24 to 0.62; 139 participants; 2 studies; low-certainty evidence). The studies did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be little or no difference in days' hospitalisation and treatment (hospitalisation: MD 3.89, 95% CI -1.20 to 8.98; 32 participants; treatment: MD 4.30, 95% CI -0.73 to 9.33; 31 participants; both low-certainty evidence). Phenobarbital versus chlorpromazine: there may be a reduction in treatment failure with phenobarbital versus chlorpromazine (RR 0.55, 95% CI 0.33 to 0.92; 138 participants; 2 studies; very low-certainty evidence), and no infant had a seizure. The studies did not report mortality and neurodevelopmental disability. One study reported there may be little or no difference in days' hospitalisation (MD 7.00, 95% CI -3.51 to 17.51; 87 participants; low-certainty evidence) and 0/100 infants had an adverse event. Phenobarbital and opioid versus opioid alone: one study reported no infants with treatment failure and no clinical seizures in either group (low-certainty evidence). The study did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be a reduction in days' hospitalisation for infants treated with phenobarbital and opioid (MD -43.50, 95% CI -59.18 to -27.82; 20 participants; low-certainty evidence). Clonidine and opioid versus opioid alone: one study reported there may be little or no difference in treatment failure with clonidine and dilute tincture of opium (DTO) versus DTO alone (RR 0.09, 95% CI 0.01 to 1.59; 80 participants; very low-certainty evidence). All five infants with treatment failure were in the DTO group. There may be little or no difference in seizures (RR 0.14, 95% CI 0.01 to 2.68; 80 participants; very low-certainty evidence). All three infants with seizures were in the DTO group. There may be little or no difference in mortality after discharge (RR 7.00, 95% CI 0.37 to 131.28; 80 participants; very low-certainty evidence). All three deaths were in the clonidine and DTO group. The study did not report neurodevelopmental disability. There may be little or no difference in days' treatment (MD -4.00, 95% CI -8.33 to 0.33; 80 participants; very low-certainty evidence). One adverse event occurred in the clonidine and DTO group. There may be little or no difference in rebound NAS after stopping treatment, although all seven cases were in the clonidine and DTO group. Clonidine and opioid versus phenobarbital and opioid: there may be little or no difference in treatment failure (RR 2.27, 95% CI 0.98 to 5.25; 2 studies, 93 participants; very low-certainty evidence). One study reported one infant in the clonidine and morphine group had a seizure, and there were no infant mortalities. The studies did not report neurodevelopmental disability. There may be an increase in days' hospitalisation and days' treatment with clonidine and opioid versus phenobarbital and opioid(hospitalisation: MD 7.13, 95% CI 6.38 to 7.88; treatment: MD 7.57, 95% CI 3.97 to 11.17; both 2 studies, 91 participants; low-certainty evidence). There may be little or no difference in adverse events (RR 1.55, 95% CI 0.44 to 5.40; 2 studies, 93 participants; very low-certainty evidence). However, there was oversedation only in the phenobarbital and morphine group; and hypotension, rebound hypertension and rebound NAS only in the clonidine and morphine group. AUTHORS' CONCLUSIONS: There is very low-certainty evidence that phenobarbital increases duration of hospitalisation and treatment, but reduces days to regain birthweight and duration of supportive care each day compared to supportive care alone. There is low-certainty evidence that phenobarbital reduces treatment failure compared to diazepam and very low-certainty evidence that  phenobarbital reduces treatment failure compared to chlorpromazine. There is low-certainty evidence of an increase in days' hospitalisation and days' treatment with clonidine and opioid compared to phenobarbital and opioid. There are insufficient data to determine the safety and incidence of adverse events for infants treated with combinations of opioids and sedatives including phenobarbital and clonidine.

The Effect of Maternal Antibodies on Clinical Response to Infection with Epizootic Hemorrhagic Disease Virus in White-Tailed Deer (Odocoileus virginianus) Fawns.

We investigated whether naturally acquired maternal antibodies to epizootic hemorrhagic disease virus serotype 2 (EHDV-2) would protect white-tailed deer (Odocoileus virginianus) fawns against infection and clinical disease following an EHDV-2 challenge. We compared viremia and clinical response in 27-47-d-old, experimentally infected fawns with and without maternally derived antibodies to EHDV-2. Mild to moderate clinical signs were observed in four seronegative (maternal antibody-negative) fawns, which were viremic from 3 to 14 d postinoculation. Individual peak blood virus titers for seronegative fawns ranged from 104.3 to 106.3 median tissue culture infective doses (TCID50)/mL. In contrast, clinical signs were not observed in seropositive (maternal antibody-positive) fawns and a transient low-level viremia (≤102.4 TCID50/mL) occurred in two of six fawns. Our results indicated that the presence of maternally derived EHDV-2 antibodies in fawns prevents or greatly reduces clinical disease and the level and duration of EHDV-2 viremia.

Vitamin D supplementation for term breastfed infants to prevent vitamin D deficiency and improve bone health.

BACKGROUND: Vitamin D deficiency is common worldwide, contributing to nutritional rickets and osteomalacia which have a major impact on health, growth, and development of infants, children and adolescents. Vitamin D levels are low in breast milk and exclusively breastfed infants are at risk of vitamin D insufficiency or deficiency. OBJECTIVES: To determine the effect of vitamin D supplementation given to infants, or lactating mothers, on vitamin D deficiency, bone density and growth in healthy term breastfed infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to 29 May 2020 supplemented by searches of clinical trials databases, conference proceedings, and citations. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs in breastfeeding mother-infant pairs comparing vitamin D supplementation given to infants or lactating mothers compared to placebo or no intervention, or sunlight, or that compare vitamin D supplementation of infants to supplementation of mothers. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 19 studies with 2837 mother-infant pairs assessing vitamin D given to infants (nine studies), to lactating mothers (eight studies), and to infants versus lactating mothers (six studies). No studies compared vitamin D given to infants versus periods of infant sun exposure. Vitamin D supplementation given to infants: vitamin D at 400 IU/day may increase 25-OH vitamin D levels (MD 22.63 nmol/L, 95% CI 17.05 to 28.21; participants = 334; studies = 6; low-certainty) and may reduce the incidence of vitamin D insufficiency (25-OH vitamin D < 50 nmol/L) (RR 0.57, 95% CI 0.41 to 0.80; participants = 274; studies = 4; low-certainty). However, there was insufficient evidence to determine if vitamin D given to the infant reduces the risk of vitamin D deficiency (25-OH vitamin D < 30 nmol/L) up till six months of age (RR 0.41, 95% CI 0.16 to 1.05; participants = 122; studies = 2), affects bone mineral content (BMC), or the incidence of biochemical or radiological rickets (all very-low certainty). We are uncertain about adverse effects including hypercalcaemia. There were no studies of higher doses of infant vitamin D (> 400 IU/day) compared to placebo. Vitamin D supplementation given to lactating mothers: vitamin D supplementation given to lactating mothers may increase infant 25-OH vitamin D levels (MD 24.60 nmol/L, 95% CI 21.59 to 27.60; participants = 597; studies = 7; low-certainty), may reduce the incidences of vitamin D insufficiency (RR 0.47, 95% CI 0.39 to 0.57; participants = 512; studies = 5; low-certainty), vitamin D deficiency (RR 0.15, 95% CI 0.09 to 0.24; participants = 512; studies = 5; low-certainty) and biochemical rickets (RR 0.06, 95% CI 0.01 to 0.44; participants = 229; studies = 2; low-certainty). The two studies that reported biochemical rickets used maternal dosages of oral D3 60,000 IU/day for 10 days and oral D3 60,000 IU postpartum and at 6, 10, and 14 weeks. However, infant BMC was not reported and there was insufficient evidence to determine if maternal supplementation has an effect on radiological rickets (RR 0.76, 95% CI 0.18 to 3.31; participants = 536; studies = 3; very low-certainty). All studies of maternal supplementation enrolled populations at high risk of vitamin D deficiency. We are uncertain of the effects of maternal supplementation on infant growth and adverse effects including hypercalcaemia. Vitamin D supplementation given to infants compared with supplementation given to lactating mothers: infant vitamin D supplementation compared to lactating mother supplementation may increase infant 25-OH vitamin D levels (MD 14.35 nmol/L, 95% CI 9.64 to 19.06; participants = 269; studies = 4; low-certainty). Infant vitamin D supplementation may reduce the incidence of vitamin D insufficiency (RR 0.61, 95% CI 0.40 to 0.94; participants = 334; studies = 4) and may reduce vitamin D deficiency (RR 0.35, 95% CI 0.17 to 0.72; participants = 334; studies = 4) but the evidence is very uncertain. Infant BMC and radiological rickets were not reported and there was insufficient evidence to determine if maternal supplementation has an effect on infant biochemical rickets. All studies enrolled patient populations at high risk of vitamin D deficiency. Studies compared an infant dose of vitamin D 400 IU/day with varying maternal vitamin D doses from 400 IU/day to > 4000 IU/day. We are uncertain about adverse effects including hypercalcaemia. AUTHORS' CONCLUSIONS: For breastfed infants, vitamin D supplementation 400 IU/day for up to six months increases 25-OH vitamin D levels and reduces vitamin D insufficiency, but there was insufficient evidence to assess its effect on vitamin D deficiency and bone health. For higher-risk infants who are breastfeeding, maternal vitamin D supplementation reduces vitamin D insufficiency and vitamin D deficiency, but there was insufficient evidence to determine an effect on bone health. In populations at higher risk of vitamin D deficiency, vitamin D supplementation of infants led to greater increases in infant 25-OH vitamin D levels, reductions in vitamin D insufficiency and vitamin D deficiency compared to supplementation of lactating mothers. However, the evidence is very uncertain for markers of bone health. Maternal higher dose supplementation (≥ 4000 IU/day) produced similar infant 25-OH vitamin D levels as infant supplementation of 400 IU/day. The certainty of evidence was graded as low to very low for all outcomes.

Pharmacological interventions for prevention and treatment of upper gastrointestinal bleeding in newborn infants.

BACKGROUND: Upper gastrointestinal bleeding is typically a mild, self-limiting condition that can affect both preterm and term neonates, although it can be severe particularly when associated with co-morbidities. Pharmacological interventions with a proton pump inhibitor (PPI), H2 receptor antagonist (H2RA), antacid, bismuth and sucralfate may have effects on both the prevention and treatment of upper gastrointestinal bleeding in infants. OBJECTIVES: To assess how different pharmacological interventions (PPIs, H2RAs, antacids, sucralfate or bismuth salts) administered to preterm and term neonates for the prevention or treatment of upper gastrointestinal bleeding to reduce morbidity and mortality compare with placebo or no treatment, supportive care, or each other. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 6), MEDLINE via PubMed (1966 to 12 July 2018), Embase (1980 to 12 July 2018), and CINAHL (1982 to 12 July 2018). We also searched clinical trial databases, conference proceedings, the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials, and online for Chinese literature articles. SELECTION CRITERIA: We selected randomised, quasi-randomised and cluster-randomised trials involving preterm and term neonates. Trials were included if they used a proton pump inhibitor, H2 receptor antagonist, antacid, sucralfate or bismuth either for the prevention or treatment of upper gastrointestinal bleeding. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of studies for inclusion, extracted data and assessed methodological quality. We conducted meta-analysis using a fixed-effect model. We used the GRADE approach to assess quality of evidence. MAIN RESULTS: Eleven studies with 818 infants met the criteria for inclusion in this review.Four trials with 329 infants assessed the use of an H2 receptor antagonist for prevention of upper gastrointestinal bleeding in high-risk newborn infants. Meta-analysis of these four trials identified a reduction in any upper gastrointestinal bleeding when using an H2 receptor antagonist (typical risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.58; typical risk difference (RD) -0.20, 95% CI -0.28 to -0.11; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 4 to 9). The quality of evidence was moderate. A single trial with 53 infants assessing prevention of upper gastrointestinal bleeding reported no difference in mortality in infants assigned H2 receptor antagonist versus no treatment; however the quality of evidence was very low.Seven trials with 489 infants assessed an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) for treatment of gastrointestinal bleeding in newborn infants. Meta-analysis of two trials (131 infants) showed no difference in mortality from use of a H2 receptor antagonist compared to no treatment. The quality of evidence was low. Meta-analysis of two trials (104 infants) showed a reduction in duration of upper gastrointestinal bleeding from use of an inhibitor of gastric acid compared to no treatment (mean difference -1.06 days, 95% CI -1.28 to -0.84). The quality of evidence was very low. Meta-analysis of six trials (451 infants) showed a reduction in continued upper gastrointestinal bleeding from use of any inhibitor of gastric acid compared to no treatment (typical RR 0.36, 95% CI 0.26 to 0.49; typical RD -0.26, 95% CI -0.33, -0.19; NNTB 4, 95% CI 3 to 5). The quality of evidence was low. There were no significant subgroup differences in duration of upper gastrointestinal bleeding or of continued upper gastrointestinal bleeding according to type of inhibitor of gastric acid. A single trial (38 infants) reported no difference in anaemia requiring blood transfusion from use of a H2 receptor antagonist compared to no treatment.Although no serious adverse events were reported from the use of a H2 receptor antagonist or proton pump inhibitor, some neonatal morbidities - including necrotising enterocolitis, ventilator-associated pneumonia, duration of ventilation and respiratory support, and duration of hospital stay - were not reported. Long-term outcome was not reported. AUTHORS' CONCLUSIONS: There is moderate-quality evidence that use of an H2 receptor antagonist reduces the risk of gastrointestinal bleeding in newborn infants at high risk of gastrointestinal bleeding. There is low-quality evidence that use of an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) reduces the duration of upper gastrointestinal bleeding and the incidence of continued gastric bleeding in newborn infants with gastrointestinal bleeding. However, there is no evidence that use of an inhibitor of gastric acid in newborn infants affects mortality or the need for blood transfusion. As no study reported the incidence of necrotising enterocolitis, ventilator- or hospital-associated pneumonia, sepsis, or long-term outcome, the safety of inhibitors of gastric acid secretion is unclear.

Infant formulas containing hydrolysed protein for prevention of allergic disease.

BACKGROUND: Infant formulas containing hydrolysed proteins have been widely advocated for preventing allergic disease in infants, in place of standard cow's milk formula (CMF). However, it is unclear whether the clinical trial evidence supports this. OBJECTIVES: To compare effects on allergic disease when infants are fed a hydrolysed formula versus CMF or human breast milk. If hydrolysed formulas are effective, to determine what type of hydrolysed formula is most effective, including extensively or partially hydrolysed formula (EHF/PHF). To determine whether infants at low or high risk of allergic disease, and whether infants receiving early short-term (first few days after birth) or prolonged formula feeding benefit from hydrolysed formulas. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 11), MEDLINE (1948 to 3 November 2017), and Embase (1974 to 3 November 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles and previous reviews for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We searched for randomised and quasi-randomised trials that compared use of a hydrolysed formula versus human milk or CMF. Outcomes with ≥ 80% follow-up of participants from eligible trials were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality and extracted data from the included studies. Fixed-effect analyses were performed. The treatment effects were expressed as risk ratio (RR) and risk difference (RD) with 95% confidence intervals and quality of evidence using the GRADE quality of evidence approach. The primary outcome was all allergic disease (including asthma, atopic dermatitis, allergic rhinitis and food allergy). MAIN RESULTS: A total of 16 studies were included.Two studies assessed the effect of three to four days infant supplementation with an EHF while in hospital after birth versus pasteurised human milk feed. A single study enrolling 90 infants reported no difference in all allergic disease (RR 1.43, 95% CI 0.38 to 5.37) or any specific allergic disease up to childhood including cow's milk allergy (CMA) (RR 7.11, 95% CI 0.35 to 143.84). A single study reported no difference in infant CMA (RR 0.87, 95% CI 0.52 to 1.46; participants = 3559). Quality of evidence was assessed as very low for all outcomes.No eligible trials compared prolonged hydrolysed formula versus human milk feeding.Two studies assessed the effect of three to four days infant supplementation with an EHF versus a CMF. A single study enrolling 90 infants reported no difference in all allergic disease (RR 1.37, 95% CI 0.33 to 5.71; participants = 77) or any specific allergic disease including CMA up to childhood. A single study reported a reduction in infant CMA of borderline significance (RR 0.62, 95% CI 0.38 to 1.00; participants = 3473). Quality of evidence was assessed as very low for all outcomes.Twelve studies assessed the effect of prolonged infant feeding with a hydrolysed formula compared with a CMF. The data showed no difference in all allergic disease in infants (typical RR 0.88, 95% CI 0.76 to 1.01; participants = 2852; studies = 8) and children (typical RR 0.85, 95% CI 0.69 to 1.05; participants = 950; studies = 2), and no difference in any specific allergic disease including infant asthma (typical RR 0.57, 95% CI 0.31 to 1.04; participants = 318; studies = 4), eczema (typical RR 0.93, 95% CI 0.79 to 1.09; participants = 2896; studies = 9), rhinitis (typical RR 0.52, 95% CI 0.14 to 1.85; participants = 256; studies = 3), food allergy (typical RR 1.42, 95% CI 0.87 to 2.33; participants = 479; studies = 2), and CMA (RR 2.31, 95% CI 0.24 to 21.97; participants = 338; studies = 1). Quality of evidence was assessed as very low for all outcomes. AUTHORS' CONCLUSIONS: We found no evidence to support short-term or prolonged feeding with a hydrolysed formula compared with exclusive breast feeding for prevention of allergic disease. Very low-quality evidence indicates that short-term use of an EHF compared with a CMF may prevent infant CMA. Further trials are recommended before implementation of this practice.We found no evidence to support prolonged feeding with a hydrolysed formula compared with a CMF for prevention of allergic disease in infants unable to be exclusively breast fed.

Lower versus higher oxygen concentrations titrated to target oxygen saturations during resuscitation of preterm infants at birth.

BACKGROUND: Initial resuscitation with air is well tolerated by most infants born at term. However, the optimal fractional inspired oxygen concentration (FiO2 - proportion of the breathed air that is oxygen) targeted to oxygen saturation (SpO2 - an estimate of the amount of oxygen in the blood) for infants born preterm is unclear. OBJECTIVES: To determine whether lower or higher initial oxygen concentrations, when titrated according to oxygen saturation targets during the resuscitation of preterm infants at birth, lead to improved short- and long-term mortality and morbidity. SEARCH METHODS: We conducted electronic searches of the Cochrane Central Register of Controlled Trials (13 October 2017), Ovid MEDLINE (1946 to 13 October 2017), Embase (1974 to 13 October 2017) and CINAHL (1982 to 13 October 2017); we also searched previous reviews (including cross-references), contacted expert informants, and handsearched journals. SELECTION CRITERIA: We included randomised controlled trials (including cluster- and quasi-randomised trials) which enrolled preterm infants requiring resuscitation following birth and allocated them to receive either lower (FiO2 < 0.4) or higher (FiO2 ≥ 0.4) initial oxygen concentrations titrated to target oxygen saturation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of studies for inclusion, extracted data and assessed methodological quality. Primary outcomes included mortality near term or at discharge (latest reported) and neurodevelopmental disability. We conducted meta-analysis using a fixed-effect model. We assessed the quality of the evidence using GRADE. MAIN RESULTS: The search identified 10 eligible trials. Meta-analysis of the 10 included studies (914 infants) showed no difference in mortality to discharge between lower (FiO2 < 0.4) and higher (FiO2 ≥ 0.4) initial oxygen concentrations targeted to oxygen saturation (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.68 to 1.63). We identified no heterogeneity in this analysis. We graded the quality of the evidence as low due to risk of bias and imprecision. There were no significant subgroup effects according to inspired oxygen concentration strata (FiO2 0.21 versus ≥ 0.4 to < 0.6; FiO2 0.21 versus ≥ 0.6 to 1.0; and FiO2 ≥ 0.3 to < 0.4 versus ≥ 0.6 to 1.0). Subgroup analysis identified a single trial that reported increased mortality from use of lower (FiO2 0.21) versus higher (FiO2 1.0) initial oxygen concentration targeted to a lowest SpO2 of less than 85%, whereas meta-analysis of nine trials targeting a lowest SpO2 of 85% to 90% found no difference in mortality.Meta-analysis of two trials (208 infants) showed no difference in neurodevelopmental disability at 24 months between infants receiving lower (FiO2 < 0.4) versus higher (FiO2 > 0.4) initial oxygen concentrations targeted to oxygen saturation. Other outcomes were incompletely reported by studies. Overall, we found no difference in use of intermittent positive pressure ventilation or intubation in the delivery room; retinopathy (damage to the retina of the eyes, measured as any retinopathy and severe retinopathy); intraventricular haemorrhage (any and severe); periventricular leukomalacia (a type of white-matter brain injury); necrotising enterocolitis (a condition where a portion of the bowel dies); chronic lung disease at 36 weeks' gestation; mortality to follow up; postnatal growth failure; and patent ductus arteriosus. We graded the quality of the evidence for these outcomes as low or very low. AUTHORS' CONCLUSIONS: There is uncertainty as to whether initiating post birth resuscitation in preterm infants using lower (FiO2 < 0.4) or higher (FiO2 ≥ 0.4) oxygen concentrations, targeted to oxygen saturations in the first 10 minutes, has an important effect on mortality or major morbidity, intubation during post birth resuscitation, other resuscitation outcomes, and long-term outcomes including neurodevelopmental disability. We assessed the quality of the evidence for all outcomes as low to very low. Further large, well designed trials are needed to assess the effect of using different initial oxygen concentrations and the effect of targeting different oxygen saturations.

Higher versus lower amino acid intake in parenteral nutrition for newborn infants.

BACKGROUND: Sick newborn and preterm infants frequently are not able to be fed enterally, necessitating parenteral fluid and nutrition. Potential benefits of higher parenteral amino acid (AA) intake for improved nitrogen balance, growth, and infant health may be outweighed by the infant's ability to utilise high intake of parenteral AA, especially in the days after birth. OBJECTIVES: The primary objective is to determine whether higher versus lower intake of parenteral AA is associated with improved growth and disability-free survival in newborn infants receiving parenteral nutrition.Secondary objectives include determining whether:• higher versus lower starting or initial intake of amino acids is associated with improved growth and disability-free survival without side effects;• higher versus lower intake of amino acids at maximal intake is associated with improved growth and disability-free survival without side effects; and• increased amino acid intake should replace non-protein energy intake (glucose and lipid), should be added to non-protein energy intake, or should be provided simultaneously with non-protein energy intake.We conducted subgroup analyses to look for any differences in the effects of higher versus lower intake of amino acids according to gestational age, birth weight, age at commencement, and condition of the infant, or concomitant increases in fluid intake. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (2 June 2017), MEDLINE (1966 to 2 June 2017), Embase (1980 to 2 June 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 2 June 2017). We also searched clinical trials databases, conference proceedings, and citations of articles. SELECTION CRITERIA: Randomised controlled trials of higher versus lower intake of AAs as parenteral nutrition in newborn infants. Comparisons of higher intake at commencement, at maximal intake, and at both commencement and maximal intake were performed. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality, and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CIs) and assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Thirty-two studies were eligible for inclusion. Six were short-term biochemical tolerance studies, one was in infants at > 35 weeks' gestation, one in term surgical newborns, and three yielding no usable data. The 21 remaining studies reported clinical outcomes in very preterm or low birth weight infants for inclusion in meta-analysis for this review.Higher AA intake had no effect on mortality before hospital discharge (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14; I2 = 0%; quality of evidence: low). Evidence was insufficient to show an effect on neurodevelopment and suggest no reported benefit (quality of evidence: very low). Higher AA intake was associated with a reduction in postnatal growth failure (< 10th centile) at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3; I2 = 22%; typical RD -0.15, 95% CI -0.27 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 50; quality of evidence: very low). Subgroup analyses found reduced postnatal growth failure in infants that commenced on high amino acid intake (> 2 to ≤ 3 g/kg/day); that occurred with increased amino acid and non-protein caloric intake; that commenced on intake at < 24 hours' age; and that occurred with early lipid infusion.Higher AA intake was associated with a reduction in days needed to regain birth weight (MD -1.14, 95% CI -1.73 to -0.56; participants = 950; studies = 13; I2 = 77%). Data show varying effects on growth parameters and no consistent effects on anthropometric z-scores at any time point, as well as increased growth in head circumference at discharge (MD 0.09 cm/week, 95% CI 0.06 to 0.13; participants = 315; studies = 4; I2 = 90%; quality of evidence: very low).Higher AA intake was not associated with effects on days to full enteral feeds, late-onset sepsis, necrotising enterocolitis, chronic lung disease, any or severe intraventricular haemorrhage, or periventricular leukomalacia. Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4; I2 = 31%; quality of evidence: very low) but no difference in severe retinopathy of prematurity.Higher AA intake was associated with an increase in positive protein balance and nitrogen balance. Potential biochemical intolerances were reported, including risk of abnormal blood urea nitrogen (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7; I2 = 6%; typical RD 0.26, 95% CI 0.20 to 0.32; number needed to treat for an additional harmful outcome (NNTH) 4; 95% CI 3 to 5; quality of evidence: high). Higher amino acid intake in parenteral nutrition was associated with a reduction in hyperglycaemia (> 8.3 mmol/L) (typical RR 0.69, 95% CI 0.49 to 0.96; participants = 505; studies = 5; I2 = 68%), although the incidence of hyperglycaemia treated with insulin was not different. AUTHORS' CONCLUSIONS: Low-quality evidence suggests that higher AA intake in parenteral nutrition does not affect mortality. Very low-quality evidence suggests that higher AA intake reduces the incidence of postnatal growth failure. Evidence was insufficient to show an effect on neurodevelopment. Very low-quality evidence suggests that higher AA intake reduces retinopathy of prematurity but not severe retinopathy of prematurity. Higher AA intake was associated with potentially adverse biochemical effects resulting from excess amino acid load, including azotaemia. Adequately powered trials in very preterm infants are required to determine the optimal intake of AA and effects of caloric balance in parenteral nutrition on the brain and on neurodevelopment.

Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis.

BACKGROUND: The effects of delayed cord clamping of the umbilical cord in preterm infants are unclear. OBJECTIVE: We sought to compare the effects of delayed vs early cord clamping on hospital mortality (primary outcome) and morbidity in preterm infants using Cochrane Collaboration neonatal review group methodology. STUDY DESIGN: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Chinese articles, cross-referencing citations, expert informants, and trial registries to July 31, 2017, for randomized controlled trials of delayed (≥30 seconds) vs early (<30 seconds) clamping in infants born <37 weeks' gestation. Before searching the literature, we specified that trials estimated to have cord milking in >20% of infants in any arm would be ineligible. Two reviewers independently selected studies, assessed bias, and extracted data. Relative risk (ie, risk ratio), risk difference, and mean difference with 95% confidence intervals were assessed by fixed effects models, heterogeneity by I2 statistics, and the quality of evidence by Grading of Recommendations, Assessment, Development, and Evaluations. RESULTS: Eighteen randomized controlled trials compared delayed vs early clamping in 2834 infants. Most infants allocated to have delayed clamping were assigned a delay of ≥60 seconds. Delayed clamping reduced hospital mortality (risk ratio, 0.68; 95% confidence interval, 0.52-0.90; risk difference, -0.03; 95% confidence interval, -0.05 to -0.01; P = .005; number needed to benefit, 33; 95% confidence interval, 20-100; Grading of Recommendations, Assessment, Development, and Evaluations = high, with I2 = 0 indicating no heterogeneity). In 3 trials in 996 infants ≤28 weeks' gestation, delayed clamping reduced hospital mortality (risk ratio, 0.70; 95% confidence interval, 0.51-0.95; risk difference, -0.05; 95% confidence interval, -0.09 to -0.01; P = .02, number needed to benefit, 20; 95% confidence interval, 11-100; I2 = 0). In subgroup analyses, delayed clamping reduced the incidence of low Apgar score at 1 minute, but not at 5 minutes, and did not reduce the incidence of intubation for resuscitation, admission temperature, mechanical ventilation, intraventricular hemorrhage, brain injury, chronic lung disease, patent ductus arteriosus, necrotizing enterocolitis, late onset sepsis or retinopathy of prematurity. Delayed clamping increased peak hematocrit by 2.73 percentage points (95% confidence interval, 1.94-3.52; P < .00001) and reduced the proportion of infants having blood transfusion by 10% (95% confidence interval, 6-13%; P < .00001). Potential harms of delayed clamping included polycythemia and hyperbilirubinemia. CONCLUSION: This systematic review provides high-quality evidence that delayed clamping reduced hospital mortality, which supports current guidelines recommending delayed clamping in preterm infants. This review does not evaluate cord milking, which may also be of benefit. Analyses of individual patient data in these and other randomized controlled trials will be critically important in reliably evaluating important secondary outcomes.

WITHDRAWN: Infant formulas containing hydrolysed protein for prevention of allergic disease and food allergy.

BACKGROUND: Allergy is common and may be associated with foods, including cow's milk formula (CMF). Formulas containing hydrolysed proteins have been used to treat infants with allergy. However, it is unclear whether hydrolysed formulas can be advocated for prevention of allergy in infants. OBJECTIVES: To compare effects on allergy and food allergy when infants are fed a hydrolysed formula versus CMF or human breast milk. If hydrolysed formulas are effective, to determine what type of hydrolysed formula is most effective, including extensively or partially hydrolysed formula (EHF/PHF). To determine which infants at low or high risk of allergy and which infants receiving early, short-term or prolonged formula feeding may benefit from hydrolysed formulas. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group supplemented by cross referencing of previous reviews and publications (updated August 2016). SELECTION CRITERIA: We searched for randomised and quasi-randomised trials that compared use of a hydrolysed formula versus human milk or CMF. Trials with ≥ 80% follow-up of participants were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We independently assessed eligibility of studies for inclusion, methodological quality and data extraction. Primary outcomes included clinical allergy, specific allergy and food allergy. We conducted meta-analysis using a fixed-effect (FE) model. MAIN RESULTS: Two studies assessed the effect of three to four days' infant supplementation with an EHF whilst in hospital after birth versus pasteurised human milk feed. Results showed no difference in infant allergy or childhood cow's milk allergy (CMA). No eligible trials compared prolonged hydrolysed formula versus human milk feeding.Two studies assessed the effect of three to four days infant supplementation with an EHF versus a CMF. One large quasi-random study reported a reduction in infant CMA of borderline significance among low-risk infants (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.38 to 1.00).Prolonged infant feeding with a hydrolysed formula compared with a CMF was associated with a reduction in infant allergy (eight studies, 2852 infants; FE RR 0.82, 95% CI 0.72 to 0.95; risk difference (RD) -0.04, 95% CI -0.08 to -0.01; number needed to treat for an additional beneficial outcome (NNTB) 25, 95% CI 12.5 to 100) and infant CMA (two studies, 405 infants; FE RR 0.38, 95% CI 0.16 to 0.86). We had substantial methodological concerns regarding studies and concerns regarding publication bias, as substantial numbers of studies including those in high-risk infants have not comprehensively reported allergy outcomes (GRADE quality of evidence 'very low').Prolonged infant feeding with a hydrolysed formula compared with a CMF was not associated with a difference in childhood allergy and led to no differences in specific allergy, including infant and childhood asthma, eczema and rhinitis and infant food allergy. Many of the analyses assessing specific allergy are underpowered.Subroup analyses showed that infant allergy was reduced in studies that enrolled infants at high risk of allergy who used a hydrolysed formula compared with a CMF; used a PHF compared with a CMF; used prolonged and exclusive feeding of a hydrolysed formula compared with a CMF; and used a partially hydrolysed whey formula compared with a CMF. Studies that enrolled infants at high risk of allergy; used a PHF compared with a CMF; used prolonged and exclusive feeding of a hydrolysed formula compared with a CMF; and used a partially hydrolysed whey formula compared with a CMF found a reduction in infant CMA. AUTHORS' CONCLUSIONS: We found no evidence to support short-term or prolonged feeding with a hydrolysed formula compared with exclusive breast feeding for prevention of allergy. Very low-quality evidence indicates that short-term use of an EHF compared with a CMF may prevent infant CMA.In infants at high risk of allergy not exclusively breast fed, very low-quality evidence suggests that prolonged hydrolysed formula feeding compared with CMF feeding reduces infant allergy and infant CMA. Studies have found no difference in childhood allergy and no difference in specific allergy, including infant and childhood asthma, eczema and rhinitis and infant food allergy.Very low-quality evidence shows that prolonged use of a partially hydrolysed formula compared with a CMF for partial or exclusive feeding was associated with a reduction in infant allergy incidence and CMA incidence, and that prolonged use of an EHF versus a PHF reduces infant food allergy.

Infant formulas containing hydrolysed protein for prevention of allergic disease and food allergy.

BACKGROUND: Allergy is common and may be associated with foods, including cow's milk formula (CMF). Formulas containing hydrolysed proteins have been used to treat infants with allergy. However, it is unclear whether hydrolysed formulas can be advocated for prevention of allergy in infants. OBJECTIVES: To compare effects on allergy and food allergy when infants are fed a hydrolysed formula versus CMF or human breast milk. If hydrolysed formulas are effective, to determine what type of hydrolysed formula is most effective, including extensively or partially hydrolysed formula (EHF/PHF). To determine which infants at low or high risk of allergy and which infants receiving early, short-term or prolonged formula feeding may benefit from hydrolysed formulas. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group supplemented by cross referencing of previous reviews and publications (updated August 2016). SELECTION CRITERIA: We searched for randomised and quasi-randomised trials that compared use of a hydrolysed formula versus human milk or CMF. Trials with ≥ 80% follow-up of participants were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We independently assessed eligibility of studies for inclusion, methodological quality and data extraction. Primary outcomes included clinical allergy, specific allergy and food allergy. We conducted meta-analysis using a fixed-effect (FE) model. MAIN RESULTS: Two studies assessed the effect of three to four days' infant supplementation with an EHF whilst in hospital after birth versus pasteurised human milk feed. Results showed no difference in infant allergy or childhood cow's milk allergy (CMA). No eligible trials compared prolonged hydrolysed formula versus human milk feeding.Two studies assessed the effect of three to four days' infant supplementation with an EHF versus a CMF. One large quasi-random study reported a reduction in infant CMA of borderline significance among low-risk infants (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.38 to 1.00).Prolonged infant feeding with a hydrolysed formula compared with a CMF was associated with a reduction in infant allergy (eight studies, 2852 infants; FE RR 0.82, 95% CI 0.72 to 0.95; risk difference (RD) -0.04, 95% CI -0.08 to -0.01; number needed to treat for an additional beneficial outcome (NNTB) 25, 95% CI 12.5 to 100) and infant CMA (two studies, 405 infants; FE RR 0.38, 95% CI 0.16 to 0.86). We had substantial methodological concerns regarding studies and concerns regarding publication bias, as substantial numbers of studies including those in high-risk infants have not comprehensively reported allergy outcomes (GRADE quality of evidence 'very low').Prolonged infant feeding with a hydrolysed formula compared with a CMF was not associated with a difference in childhood allergy and led to no differences in specific allergy, including infant and childhood asthma, eczema and rhinitis and infant food allergy. Many of the analyses assessing specific allergy are underpowered.Subroup analyses showed that infant allergy was reduced in studies that enrolled infants at high risk of allergy who used a hydrolysed formula compared with a CMF; used a PHF compared with a CMF; used prolonged and exclusive feeding of a hydrolysed formula compared with a CMF; and used a partially hydrolysed whey formula compared with a CMF. Studies that enrolled infants at high risk of allergy; used a PHF compared with a CMF; used prolonged and exclusive feeding of a hydrolysed formula compared with a CMF; and used a partially hydrolysed whey formula compared with a CMF found a reduction in infant CMA. AUTHORS' CONCLUSIONS: We found no evidence to support short-term or prolonged feeding with a hydrolysed formula compared with exclusive breast feeding for prevention of allergy. Very low-quality evidence indicates that short-term use of an EHF compared with a CMF may prevent infant CMA.In infants at high risk of allergy not exclusively breast fed, very low-quality evidence suggests that prolonged hydrolysed formula feeding compared with CMF feeding reduces infant allergy and infant CMA. Studies have found no difference in childhood allergy and no difference in specific allergy, including infant and childhood asthma, eczema and rhinitis and infant food allergy.Very low-quality evidence shows that prolonged use of a partially hydrolysed formula compared with a CMF for partial or exclusive feeding was associated with a reduction in infant allergy incidence and CMA incidence, and that prolonged use of an EHF versus a PHF reduces infant food allergy.

Polyunsaturated fatty acid supplementation in infancy for the prevention of allergy.

BACKGROUND: Early dietary intakes may influence the development of allergic disease. It is important to determine if dietary polyunsaturated fatty acids (PUFAs) given as supplements or added to infant formula prevent the development of allergy. OBJECTIVES: To determine the effect of higher PUFA intake during infancy to prevent allergic disease. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9), MEDLINE (1966 to 14 September 2015), EMBASE (1980 to 14 September 2015) and CINAHL (1982 to 14 September 2015). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared the use of a PUFA with no PUFA in infants for the prevention of allergy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality and extracted data from the included studies. We used fixed-effect analyses. The treatment effects were expressed as risk ratio (RR) with 95% confidence intervals (CI). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: The search found 17 studies that assessed the effect of higher versus lower intake of PUFAs on allergic outcomes in infants. Only nine studies enrolling 2704 infants reported allergy outcomes that could be used in meta-analyses. Of these, there were methodological concerns for eight.In infants up to two years of age, meta-analyses found no difference in incidence of all allergy (1 study, 323 infants; RR 0.96, 95% CI 0.73 to 1.26; risk difference (RD) -0.02, 95% CI -0.12 to 0.09; heterogeneity not applicable), asthma (3 studies, 1162 infants; RR 1.04, 95% CI 0.80 to 1.35, I2 = 0%; RD 0.01, 95% CI -0.04 to 0.05, I2 = 0%), dermatitis/eczema (7 studies, 1906 infants; RR 0.93, 95% CI 0.82 to 1.06, I2 = 0%; RD -0.02, 95% CI -0.06 to 0.02, I2 = 0%) or food allergy (3 studies, 915 infants; RR 0.81, 95% CI 0.56 to 1.19, I2 = 63%; RD -0.02, 95% CI -0.06 to 0.02, I2 = 74%). There was a reduction in allergic rhinitis (2 studies, 594 infants; RR 0.47, 95% CI 0.23 to 0.96, I2 = 6%; RD -0.04, 95% CI -0.08 to -0.00, I2 = 54%; number needed to treat for an additional beneficial outcome (NNTB) 25, 95% CI 13 to ∞).In children aged two to five years, meta-analysis found no difference in incidence of all allergic disease (2 studies, 154 infants; RR 0.69, 95% CI 0.47 to 1.02, I2 = 43%; RD -0.16, 95% CI -0.31 to -0.00, I2 = 63%; NNTB 6, 95% CI 3 to ∞), asthma (1 study, 89 infants; RR 0.45, 95% CI 0.20 to 1.02; RD -0.20, 95% CI -0.37 to -0.02; heterogeneity not applicable; NNTB 5, 95% CI 3 to 50), dermatitis/eczema (2 studies, 154 infants; RR 0.65, 95% CI 0.34 to 1.24, I2 = 0%; RD -0.09 95% CI -0.22 to 0.04, I2 = 24%) or food allergy (1 study, 65 infants; RR 2.27, 95% CI 0.25 to 20.68; RD 0.05, 95% CI -0.07 to 0.16; heterogeneity not applicable).In children aged two to five years, meta-analysis found no difference in prevalence of all allergic disease (2 studies, 633 infants; RR 0.98, 95% CI 0.81 to 1.19, I2 = 36%; RD -0.01, 95% CI -0.08 to 0.07, I2 = 0%), asthma (2 studies, 635 infants; RR 1.12, 95% CI 0.82 to 1.53, I2 = 0%; RD 0.02, 95% CI -0.04 to 0.09, I2 = 0%), dermatitis/eczema (2 studies, 635 infants; RR 0.81, 95% CI 0.59 to 1.09, I2 = 0%; RD -0.04 95% CI -0.11 to 0.02, I2 = 0%), allergic rhinitis (2 studies, 635 infants; RR 1.02, 95% CI 0.83 to 1.25, I2 = 0%; RD 0.01, 95% CI -0.06 to 0.08, I2 = 0%) or food allergy (1 study, 119 infants; RR 0.27, 95% CI 0.06 to 1.19; RD -0.10, 95% CI -0.20 to -0.00; heterogeneity not applicable; NNTB 10, 95% CI 5 to ∞). AUTHORS' CONCLUSIONS: There is no evidence that PUFA supplementation in infancy has an effect on infant or childhood allergy, asthma, dermatitis/eczema or food allergy. However, the quality of evidence was very low. There was insufficient evidence to determine an effect on allergic rhinitis.

Chest shielding for prevention of a haemodynamically significant patent ductus arteriosus in preterm infants receiving phototherapy.

BACKGROUND: Patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. Phototherapy is a common treatment for jaundice in preterm infants. However, phototherapy has been associated with failure of closure of the ductus arteriosus in preterm infants. OBJECTIVES: To determine if chest shielding of preterm infants receiving phototherapy reduces the incidence of clinically and/or haemodynamically significant PDA and reduces morbidity secondary to PDA. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library; 2015, Issue 3), MEDLINE, EMBASE, CINAHL, previous reviews, cross-references, abstracts, proceedings of scientific meetings, and trial registries through March 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster-RCTs, or quasi-RCTs of chest shielding during phototherapy compared to sham shielding or no shielding for the prevention of a haemodynamically or clinically significant PDA in preterm infants. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for eligibility and quality and extracted data. We defined a clinically significant PDA as the presence of a PDA with clinical signs of an effect on organ function attributable to the ductus arteriosus. We defined a haemodynamically significant PDA as clinical and/or echocardiographic signs of a significant ductus arteriosus effect on blood flow. MAIN RESULTS: We included two small trials enrolling very preterm infants (Rosenfeld 1986; Travadi 2006). We assessed both as at high risk of bias. No study reported clinically significant PDA, defined as the presence of a PDA with clinical symptoms or signs attributable to the effect of a ductus arteriosus on organ function. Rosenfeld 1986 reported a non-significant reduction in haemodynamically significant PDA with left atrial to aortic root ratio greater than 1.2 (risk ratio (RR) 0.23, 95% confidence interval (CI) 0.05 to 1.01; 74 infants) but a statistically significant risk difference (RD -0.18, 95% CI -0.34 to -0.03; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 3 to 33). Rosenfeld 1986 reported a significant reduction in PDA detected by murmur (RR 0.50, 95% CI 0.29 to 0.88; RD -0.30, 95% CI -0.52 to -0.08; NNTB 3, 95% CI 2 to 12; 74 infants). Rosenfeld 1986 reported a significant reduction in treatment with indomethacin (RR 0.12, 95% CI 0.02 to 0.88; RD -0.21, 95% CI -0.35 to -0.06; NNTB 5, 95% CI 3 to 17; 74 infants), and only one infant had a ductal ligation in the no-shield group. There were no other significant outcomes, including mortality to discharge or 28 days, days in oxygen, days on mechanical ventilation, days in hospital, intraventricular haemorrhage, retinopathy of prematurity, or exchange transfusion. AUTHORS' CONCLUSIONS: The available evidence is very low quality and insufficient to assess the safety or efficacy of chest shield during phototherapy for prevention of PDA in preterm infants. Further trials of chest shielding are warranted, particularly in settings where infants are not receiving prophylactic or early echocardiographic targeted cyclo-oxygenase inhibitors for PDA.