Diazoxide for Severe or Recurrent Neonatal Hypoglycemia: A Randomized Clinical Trial.

Importance: Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. Objective: To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia. Design, Setting, and Participants: This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours). Interventions: Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol. Main Outcome and Measures: The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks. Results: Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo. Conclusions and Relevance: In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo. Trial Registration: ANZCTR.org.au Identifier: ACTRN12620000129987.

Early Breathing in Very Preterm Infants during Deferred Cord Clamping (DCC) Is Related to Gestational Age and Is Not Independently Associated with Important Neonatal Outcomes: A 5-Year Cohort Study.

Deferred cord clamping (DCC) has been associated with reduced mortality in preterm infants, and a period of at least 30 s has been recommended before clamping. However, preterm infants assessed as being in need of resuscitation have often had earlier cord clamping. In this study, we aimed to compare neonatal outcomes for preterm infants undergoing DCC who established early breathing movements compared to those who were not breathing. After a 5 yr recruitment period, we recently completed the ABC study, in which preterm infants <31 weeks undergoing 50 s of DCC who were not breathing by 15 s of age were randomised into two groups: one received intermittent positive pressure ventilation (IPPV) and the other was a standard group, which received no breathing support. The outcomes in the two groups were similar, and for the present analysis, the groups were combined. Infants in the ABC study were compared with the cohort excluded from the original ABC study because they were breathing by 15 s (called the Breathing Before Clamping or BBC group). There were significant differences in demographics between the ABC and BBC groups. Spontaneous preterm labour was more common in the BBC group, and these infants were more likely to be delivered vaginally. Gestational age and birth weight were significantly higher in the BBC group (p < 0.01). Soon after birth, Apgar scores were significantly higher in the BBC group, with a lower base deficit on first obtained blood gas, and a smaller proportion were intubated in the delivery room. Fewer BBC infants were hypothermic (<36.5 °C) on admission. Multivariate regression analysis indicated whether infants were breathing or not at 15 s of age was linked predominantly to gestation. Important neonatal outcomes and a composite of these outcomes (mortality, severe intraventricular haemorrhage, bronchopulmonary dysplasia) were not significantly different between the ABC and BBC groups (odds ratio for the composite outcome was 1.77 CI 0.84-3.76 corrected for gestation). For very preterm infants undergoing DCC, important neonatal outcomes were related to gestational age and not independently associated with early breathing. There was a small group (7% of total) who were deemed compromised at birth and did not undergo DCC. These infants had significantly worse neonatal outcomes.

Impact of Gestational Diabetes Detection Thresholds on Infant Growth and Body Composition: A Prospective Cohort Study Within a Randomized Trial.

OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with offspring metabolic disease, including childhood obesity, but causal mediators remain to be established. We assessed the impact of lower versus higher thresholds for detection and treatment of GDM on infant risk factors for obesity, including body composition, growth, nutrition, and appetite. RESEARCH DESIGN AND METHODS: In this prospective cohort study within the Gestational Diabetes Mellitus Trial of Diagnostic Detection Thresholds (GEMS), pregnant women were randomly allocated to detection of GDM using the lower criteria of the International Association of Diabetes and Pregnancy Study Groups or higher New Zealand criteria (ACTRN12615000290594). Randomly selected control infants of women without GDM were compared with infants exposed to A) GDM by lower but not higher criteria, with usual treatment for diabetes in pregnancy; B) GDM by lower but not higher criteria, untreated; or C) GDM by higher criteria, treated. The primary outcome was whole-body fat mass at 5-6 months. RESULTS: There were 760 infants enrolled, and 432 were assessed for the primary outcome. Fat mass was not significantly different between control infants (2.05 kg) and exposure groups: A) GDM by lower but not higher criteria, treated (1.96 kg), adjusted mean difference (aMD) -0.09 (95% CI -0.29, 0.10); B) GDM by lower but not higher criteria, untreated (1.94 kg), aMD -0.15 (95% CI -0.35, 0.06); and C) GDM detected and treated using higher thresholds (1.87 kg), aMD -0.17 (95% CI -0.37, 0.03). CONCLUSIONS: GDM detected using lower but not higher criteria, was not associated with increased infant fat mass at 5-6 months, regardless of maternal treatment. GDM detected and treated using higher thresholds was also not associated with increased fat mass at 5-6 months.

Determinants of handgrip strength at age 2 years in children born moderate and late preterm and associations with neurodevelopmental outcomes.

BACKGROUND: Handgrip strength (HGS) indicates current and future health. Although preterm infants have an increased risk of poor grip strength in later life, its determinants and relationship with neurodevelopment are not well understood. AIMS: To determine HGS in children born preterm and explore the relationship of HGS with demography, anthropometry, nutritional factors, and neurodevelopmental outcomes. STUDY DESIGN: A prospective cohort study of moderate-late preterm babies enrolled in a randomised trial of nutritional support strategies, the DIAMOND trial. SUBJECTS: A total of 116 children born between 32 and 35 weeks' gestation, whose HGS was measured at 2 years' corrected age. OUTCOME MEASURES: HGS was measured using a dynamometer, and neurodevelopment was assessed using the Bayley Scales of Infant Development-III. Anthropometry and body composition were assessed at birth, discharge, and at 4 months' and 2 years' corrected age. Information on demographics and breastfeeding practices, including type of milk at discharge and duration of exclusive breastfeeding, was collected using questionnaires. RESULTS: The mean (standard deviation) HGS was 2.26 (1.07) kg. The Bayley scores were < 85 (-1 standard deviation) in 6 %, 20 %, and 1 % for the cognitive, language, and motor scales, respectively. Multiple regression analysis revealed that HGS was positively associated with language and motor scores (p < .05) after adjusting for confounding factors. HGS was not associated with sex, anthropometry, body composition, or breastfeeding practices. Maternal education was independently associated with HGS (p < .01). CONCLUSIONS: HGS at age 2 years in children born moderate-late preterm is associated with language and motor development and maternal education level.

Effect of Breathing Support in Very Preterm Infants Not Breathing During Deferred Cord Clamping: A Randomized Controlled Trial (The ABC Study).

OBJECTIVE: To determine if providing respiratory support to very preterm infants who fail to breathe regularly during deferred cord clamping (DCC) decreased red cell transfusion. STUDY DESIGN: Infants less than 31 weeks of gestation undergoing DCC who were apneic or not breathing regularly at 15 seconds underwent stratified randomization. Pale, limp, and nonresponsive infants were excluded. The standard group received gentle stimulation in a neutral position for 50 seconds; the intervention group received intermittent positive pressure ventilation via face mask and T piece from 20 to 50 seconds of age with a fractional inspired oxygen of 0.3. The primary outcome was the proportion transfused, with a secondary composite outcome of death, severe intraventricular hemorrhage, or chronic lung disease. RESULTS: Of 311 assessed infants, 113 met the inclusion criteria and were studied; 57 received the intervention and 56 standard treatment. Patient characteristics were similar. Overall, 105 infants (93%) received the intended 50 seconds DCC (54 in the intervention group and 51 in the standard group). Rates of transfusion were similar (28% vs 30% in the intervention vs control groups), as were rates of the composite outcome (46% vs 38% in the intervention vs the control arms; P = .45). CONCLUSIONS: Providing breathing support during 50 seconds of DCC in this single-center cohort seemed to be safe and feasible, but did not decrease the transfusion rates or improve outcomes. TRIAL REGISTRATION: http://www.anzctr.org.au/ACTRN12615001026516.aspx.

Association of socio-economic status and ethnicity with mortality and morbidity of premature infants admitted to neonatal intensive care in South Auckland, New Zealand.

AIM: Socio-economic status (SES) and ethnicity have been associated with worse maternal and fetal outcomes. Counties Manukau is a region of New Zealand which has a high portion of the population living in areas of low SES and has a higher population of ethnic minorities (Pacific Islander, Asian and Maaori). To determine whether SES and ethnicity are associated with worse mortality and morbidity in preterm infants in Counties Manukau Hospital, New Zealand. METHODS: This retrospective cohort study compared the infants of mothers who live in the most deprived neighbourhoods to the infants of mothers who live in the least deprived neighbourhoods. Infants born between 2000 and 2019 were included if <30 weeks gestation or <1500 g and born in hospital. Primary outcome was combined mortality/morbidity. RESULTS: Univariate analysis showed demographic differences between the SES and ethnic groups, for example maternal age and maternal smoking. Using logistic regression, SES was not associated with worse neonatal outcomes for the most deprived SES (n = 624) compared to least deprived SES (n = 164). Ethnicity (n = 1326) was not associated with worse neonatal outcomes. Gestational age and maternal smoking were associated with neonatal mortality/morbidity; gestational age and antenatal steroids were associated with neonatal mortality. It was notable that the proportion of the study population in the less deprived groups used for the comparisons was relatively low. CONCLUSIONS: For preterm, in-hospital births in Counties Manukau over a 20-year period, neonatal outcomes were the same regardless of SES or ethnicity.

Thresholds for blood transfusion in extremely preterm infants: A review of the latest evidence from two large clinical trials.

There are two recently completed large randomized clinical trials of blood transfusions in the preterm infants most at risk of requiring them. Liberal and restrictive strategies were compared with composite primary outcome measures of death and neurodevelopmental impairment. Infants managed under restrictive guidelines fared no worse in regard to mortality and neurodevelopment in early life. The studies had remarkably similar demographics and used similar transfusion guidelines. In both, there were fewer transfusions in the restrictive arm. Nevertheless, there were large differences between the studies in regard to transfusion exposure with almost 3 times the number of transfusions per participant in the transfusion of prematures (TOP) study. Associated with this, there were differences between the studies in various outcomes. For example, the combined primary outcome of death or neurodevelopmental impairment was more likely to occur in the TOP study and the mortality rate itself was considerably higher. Whilst the reasons for these differences are likely multifactorial, it does raise the question as to whether they could be related to the transfusions themselves? Clearly, every effort should be made to reduce exposure to transfusions and this was more successful in the Effects of Transfusion Thresholds on Neurocognitive Outcomes (ETTNO) study. In this review, we look at factors which may explain these transfusion differences and the differences in outcomes, in particular neurodevelopment at age 2 years. In choosing which guidelines to follow, centers using liberal guidelines should be encouraged to adopt more restrictive ones. However, should centers with more restrictive guidelines change to ones similar to those in the studies? The evidence for this is less compelling, particularly given the wide range of transfusion exposure between studies. Individual centers already using restrictive guidelines should assess the validity of the findings in light of their own transfusion experience. In addition, it should be remembered that the study guidelines were pragmatic and acceptable to a large number of centers. The major focus in these guidelines was on hemoglobin levels which do not necessarily reflect tissue oxygenation. Other factors such as the level of erythropoiesis should also be taken into account before deciding whether to transfuse.

Oral diazoxide versus placebo for severe or recurrent neonatal hypoglycaemia: Neonatal Glucose Care Optimisation (NeoGluCO) study - a randomised controlled trial.

INTRODUCTION: Infants with severe or recurrent transitional hypoglycaemia continue to have high rates of adverse neurological outcomes and new treatment approaches are needed that target the underlying pathophysiology. Diazoxide is one such treatment that acts on the pancreatic ß-cell in a dose-dependent manner to decrease insulin secretion. METHODS AND ANALYSIS: Phase IIB, double-blind, two-arm, parallel, randomised trial of diazoxide versus placebo in neonates ≥35 weeks' gestation for treatment of severe (blood glucose concentration (BGC)<1.2 mmol/L or BGC 1.2 to <2.0 mmol/L despite two doses of buccal dextrose gel and feeding in a single episode) or recurrent (≥3 episodes <2.6 mmol/L in 48 hours) transitional hypoglycaemia. Infants are loaded with diazoxide 5 mg/kg orally and then commenced on a maintenance dose of 1.5 mg/kg every 12 hours, or an equal volume of placebo. The intervention is titrated from the third maintenance dose by protocol to target BGC in the range of 2.6-5.4 mmol/L. The primary outcome is time to resolution of hypoglycaemia, defined as the first point at which the following criteria are met concurrently for ≥24 hours: no intravenous fluids, enteral bolus feeding and normoglycaemia. Groups will be compared for the primary outcome using Cox's proportional hazard regression analysis, expressed as adjusted HR with a 95% CI. ETHICS AND DISSEMINATION: This trial has been approved by the Health and Disability Ethics Committees of New Zealand (19CEN189). Findings will be disseminated in peer-reviewed journals, to clinicians and researchers at local and international conferences and to the public. TRIAL REGISTRATION NUMBER: ACTRN12620000129987.

Performance Characteristics of DOAC-Remove for Neutralization of the Effects of Apixaban and Rivaroxaban in Lupus Anticoagulant Assays.

OBJECTIVES: This study established the performance characteristics of DOAC-Remove for neutralization of the effects of rivaroxaban and apixaban in lupus anticoagulant (LAC) testing. METHODS: Normal donor, LAC control, and patient samples were spiked with rivaroxaban or apixaban to simulate their effects on the dilute Russell's viper venom time (dRVVT), activated partial thromboplastin time (APTT), and dilute prothrombin time (dPT). Anti-Xa activity was measured after spiking and after DOAC-Remove neutralization. Accuracy, complex precision, and reference interval verification were evaluated. RESULTS: DOAC-Remove neutralized rivaroxaban and apixaban concentrations as high as 415 ng/mL and 333 ng/mL, respectively. Percentage positive and negative agreement between the baseline and postneutralization interpretations were 75% or higher for the dRVVT and APTT methods but not for the dPT method. Coefficients of variation (CVs) were 10% or less for all assays except the Staclot-LA delta, which had a standard deviation of 2.5 seconds or CV of 25% or less depending on the level. The laboratory's reference intervals were verified for the dRVVT and APTT assays after DOAC-Remove treatment but not for the dPT assays. CONCLUSIONS: DOAC-Remove appears to have acceptable performance characteristics for neutralizing the effects of rivaroxaban and apixaban in the dRVVT and APTT methods but not in the dPT method.

An unusual case of anti-D detection in two consecutive D+ patient samples: Antibody carryover on an automated gel platform.

BACKGROUND: Laboratory results can be affected by sample to sample carryover. Carryover of different analytes occurring in automated clinical chemistry, immunology, hematology, and molecular laboratories is well described. However, carryover in a transfusion service laboratory is not reported in medical literature. MATERIALS AND METHODS: Immunohematology testing results, demographic data, and clinical data were reviewed on three patients retrospectively from 2015 to 2019. RESULTS: Type and screen samples tested on automated gel platform from two D+ patients were affected by anti-D carryover from a patient sample with a very high-titer anti-D. Additional immunohematology and molecular testing confirmed that anti-D in samples of two D+ patients was due to carryover. CONCLUSION: A case of anti-D carryover caused false detection of anti-D in two D+ patients. Carryover can have implications for patient management. Transfusion laboratory staff need to be aware of it and investigate any unexpected results further.

The Assisted Breathing before Cord Clamping (ABC) Study Protocol.

Major physiologic changes occur during the transition after birth. For preterm infants, current understanding favours allowing the initial changes to occur prior to cord clamping. Amongst other improved outcomes, systematic reviews have indicated a significant reduction in neonatal blood transfusions following delayed cord clamping. This may be due to a placental transfusion, facilitated by the onset of respiration. If breathing is compromised, placental transfusion may be reduced, resulting in a greater red cell transfusion rate. We designed a randomised trial to investigate whether assisting respiration in this high-risk group of babies would decrease blood transfusion and improve outcomes. The Assisted Breathing before Cord Clamping (ABC) study is a single-centre randomised controlled trial. Preterm infants < 31 weeks that have not established regular breathing before 15 s are randomised to a standard or intervention group. The intervention is intermittent positive pressure ventilation via T piece for 30 s, whilst standard management consists of 30 s of positioning and gentle stimulation. The cord is clamped at 50 s in both groups. The primary outcome is the proportion of infants in each group receiving blood transfusion during the neonatal admission. Secondary outcomes include requirement for resuscitation, the assessment of circulatory status and neonatal outcomes.

Probiotics for Prevention of Severe Necrotizing Enterocolitis: Experience of New Zealand Neonatal Intensive Care Units.

Introduction: Necrotizing enterocolitis (NEC) affects mainly preterm infants, has a multifactorial etiology and is associated with intestinal dysbiosis and disordered immunity. Use of probiotics for prophylaxis is beneficial with studies indicating reduction in NEC ≥ stage 2, late onset sepsis (LOS) and mortality. However, not all studies have shown a reduction, there are questions regarding which probiotic to use, whether infants <1,000 g benefit and the risk of probiotic sepsis. All neonatal intensive care units in New Zealand (NZ) use probiotics and contribute to an international database (Australian and New Zealand Neonatal Network or ANZNN). Objective: To use ANZNN data to investigate the experience of NZ neonatal units with probiotics for NEC prevention in a setting where the baseline incidence of severe NEC was low, to compare results of 2 commonly used probiotic regimes and report on the extremely low birth weight subgroup. Method: Outcomes before (Pre group 2007-2010) and after (Probiotic group 2013-2015) starting routine probiotics for preterm infants <1,500 g or <32 weeks were compared. Clinicians reviewed cases to ensure they met database criteria. Five units used Infloran (Bifidobacterium bifidum and Lactobacillus acidophilus) and 1 unit used Lactobacillus GG (LGG) and bovine lactoferrin (bLF). Results: Four thousand five hundred and twenty nine infants were included and Pre and Probiotic groups were well-balanced with regard to gestation, birth weight and gender. The incidence of NEC in the Probiotic group was 1.6 and 2.7% in the pre group (corrected OR 0.62 CI 0.41-0.94). There was one case of probiotic sepsis. There was no significant difference between the Infloran and LGG/bLF combinations in regard to observed NEC rates. Late onset sepsis rates were significantly lower in the Probiotic group (p < 0.01). Conclusions: Introduction of probiotics for preterm infants in NZ has been associated with significant reductions in NEC and late onset sepsis.

Correlation of Thromboelastography with Apparent Rivaroxaban Concentration: Has Point-of-Care Testing Improved?

BACKGROUND: Concern remains over reliable point-of-care testing to guide reversal of rivaroxaban, a commonly used factor Xa inhibitor, in high-acuity settings. Thromboelastography (TEG), a point-of-care viscoelastic assay, may have the ability to detect the anticoagulant effect of rivaroxaban. The authors ascertained the association of apparent rivaroxaban concentration with thromboelastography reaction time, i.e., time elapsed from blood sample placement in analyzer until beginning of clot formation, as measured using TEG and TEG6S instruments (Haemonetics Corporation, USA), hypothesizing that reaction time would correlate to degree of functional factor Xa impairment. METHODS: The authors prospectively performed a diagnostic accuracy study comparing coagulation assays to apparent (i.e., indirectly assessed) rivaroxaban concentration in trauma patients with and without preinjury rivaroxaban presenting to a single center between April 2016 and July 2018. Blood samples at admission and after reversal or 24 h postadmission underwent TEG, TEG6S, thrombin generation assay, anti-factor Xa chromogenic assay, prothrombin time (PT), and ecarin chromogenic assay testing. The authors determined correlation of kaolin TEG, TEG6S, and prothrombin time to apparent rivaroxaban concentration. Receiver operating characteristic curve compared capacity to distinguish therapeutic rivaroxaban concentration (i.e., greater than or equal to 50 ng/ml) from nontherapeutic concentrations. RESULTS: Eighty rivaroxaban patients were compared to 20 controls. Significant strong correlations existed between rivaroxaban concentration and TEG reaction time (ρ = 0.67; P < 0.001), TEG6S reaction time (ρ = 0.68; P < 0.001), and prothrombin time (ρ = 0.73; P < 0.001), however reaction time remained within the defined normal range for the assay. Rivaroxaban concentration demonstrated strong but not significant association with coagulation assays postreversal (n = 9; TEG reaction time ρ = 0.62; P = 0.101; TEG6S reaction time ρ = 0.57; P = 0.112) and small nonsignificant association for controls (TEG reaction time: ρ = -0.04; P = 0.845; TEG6S reaction time: ρ = -0.09; P = 0.667; PT-neoplastine: ρ = 0.19; P = 0.301). Rivaroxaban concentration (area under the curve, 0.91) and TEG6S reaction time (area under the curve, 0.84) best predicted therapeutic rivaroxaban concentration and exhibited similar receiver operating characteristic curves (P = 0.180). CONCLUSIONS: Although TEG6S demonstrates significant strong correlation with rivaroxaban concentration, values within normal range limit clinical utility rendering rivaroxaban concentration the gold standard in measuring anticoagulant effect.

Use of Heated Humidified Gases for Early Stabilization of Preterm Infants: A Meta-Analysis.

Background: Large observational studies in preterm infants have shown an increase in mortality and morbidity when admission temperature is below 36.5°C. Recent randomized controlled studies have shown a reduction in admission hypothermia and an increase in the number of infants admitted with normal temperature (36.5-37.5°C) when heated humidified gases were used for initial stabilization of preterm infants. Objective: The goal of this study was to perform a meta-analysis of published randomized trials using heated humidified gas compared to cold dry gas in preterm infants immediately after birth and during transport to the neonatal unit. Specific research aims were to determine the magnitude of the reduction in hypothermia and to examine neonatal outcomes including mortality. Methods: A literature search was conducted in accordance with the standard methods of the Cochrane Neonatal Work Group. Randomized trials were identified and data entered into RevMan5. A fixed effects statistical model was used. Risk of bias was assessed for included studies and the GRADE approach used to determine quality of evidence. The primary outcome was admission hypothermia (< 36.5°C). Secondary outcomes included admission temperature in the normothermic range (36.5-37.5°C) and neonatal outcomes including mortality. Results: Two studies met inclusion criteria and a total of 476 preterm infants were enrolled, all of whom were < 32 weeks gestation. Studies were not blinded but the overall risk of bias was low. Admission hypothermia was reduced by 36% (CI 17-50%), while admission normothermia was significantly increased. GRADE quality of evidence was high for these outcomes. The number of infants with more severe hypothermia (< 35.5°C) was significantly reduced (RR 0.32 CI 0.14-0.73). In addition, preterm infants < 28 weeks had significantly less admission hypothermia (RR 0.61 CI 0.42, 0.90) Mortality and measures of respiratory outcome were not significantly different (studies were not powered for these outcomes), though there was a trend to improvement in all respiratory measures assessed. There were no significant adverse events and no increase in admission hyperthermia (>37.5°C). Conclusions: Heating and humidification of inspired gases immediately after birth and during transport to the neonatal unit improves admission temperature in preterm infants. Consideration should be given to incorporating this technique into other strategies (e.g., use of plastic wrap) designed to keep preterm infants warm on admission to the neonatal unit.

The DIAMOND trial - DIfferent Approaches to MOderate & late preterm Nutrition: Determinants of feed tolerance, body composition and development: protocol of a randomised trial.

BACKGROUND: Babies born at moderate-late preterm gestations account for > 80% of all preterm births. Although survival is excellent, these babies are at increased risk of adverse neurodevelopmental outcomes. They also are at increased risk of adverse long-term health outcomes, such as cardiovascular disease, obesity and diabetes. There is little evidence guiding optimal nutritional practices in these babies; practice, therefore, varies widely. This factorial design clinical trial will address the role of parenteral nutrition, milk supplementation and exposure of the preterm infant to taste and smell with each feed on time to tolerance of full feeds, adiposity, and neurodevelopment at 2 years. METHODS/DESIGN: The DIAMOND trial is a multi-centre, factorial, randomised, controlled clinical trial. A total of 528 babies born between 32+ 0 and 35+ 6 weeks' gestation receiving intravenous fluids and whose mothers intend to breastfeed will be randomised to one of eight treatment conditions that include a combination of each of the three interventions: (i) intravenous amino acid solution vs. intravenous dextrose solution until full milk feeds established; (ii) milk supplement vs. exclusive breastmilk, and (iii) taste/smell given or not given before gastric tube feeds. Babies will be excluded if a particular mode of nutrition is clinically indicated or there is a congenital abnormality. Primary study outcome: For parenteral nutrition and milk supplement interventions, body composition at 4 months' corrected age. For taste/smell intervention, time to full enteral feeds defined as 150 ml.kg- 1.day- 1 or exclusive breastfeeding. SECONDARY OUTCOMES: Days to full sucking feeds; days in hospital; body composition at discharge; growth to 2 years' corrected age; development at 2 years' corrected age; breastfeeding rates. DISCUSSION: This trial will provide the first direct evidence to inform feeding practices in moderate- to late-preterm infants that will optimise their growth, metabolic and developmental outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12616001199404 . This trial is endorsed by the IMPACT clinical trials network ( https://impact.psanz.com.au ).

Provision of respiratory support compared to no respiratory support before cord clamping for preterm infants.

BACKGROUND: Placental transfusion (by means of delayed cord clamping (DCC), cord milking, or cord stripping) confers benefits for preterm infants. It is not known if providing respiratory support to preterm infants before cord clamping improves outcomes. OBJECTIVES: To assess the efficacy and safety of respiratory support provided during DCC compared with no respiratory support during placental transfusion (in the form of DCC, milking, or stripping) in preterm infants immediately after delivery. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL, 2017, Issue 5), MEDLINE via PubMed (1966 to 19 June 2017), Embase (1980 to 19 June 2017), and CINAHL (1982 to 19 June 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: Randomized, cluster randomized, or quasi-randomized controlled trials enrolling preterm infants undergoing DCC, where one of the groups received respiratory support before cord clamping and the control group received no respiratory support before cord clamping. DATA COLLECTION AND ANALYSIS: All review authors assisted with data collection, assessment, and extraction. Two review authors assessed the quality of evidence using the GRADE approach. We contacted study authors to request missing information. MAIN RESULTS: One study fulfilled the review criteria. In this study, 150 preterm infants of less than 32 weeks' gestation undergoing 60 second DCC were randomized to a group who received respiratory support in the form of continuous positive airway pressure (CPAP) or positive pressure ventilation during DCC and a group that did not receive respiratory support during the procedure. Mortality during hospital admission was not significantly different between groups with wide confidence intervals (CI) for magnitude of effect (risk ratio (RR) 1.67, 95% CI 0.41 to 6.73). The study did not report neurodevelopmental disability and death or disability at two to three years of age. There were no significant differences between groups in condition at birth (Apgar scores or intubation in the delivery room), use of inotropic agents (RR 1.25, CI 0.63 to 2.49), and receipt of blood transfusion (RR 1.03, 95% CI 0.70 to 1.54). In addition, there were no significant differences in the incidences of any intraventricular haemorrhage (RR 1.50, 95% CI 0.65 to 3.46) and severe intraventricular haemorrhage (RR 1.33, 95% CI 0.31 to 5.75). Several continuous variables were reported in subgroups depending on method of delivery. Unpublished data for each group as a whole was made available and showed peak haematocrit in the first 24 hours and duration of phototherapy did not differ significantly. Overall, the quality of evidence for several key neonatal outcomes (e.g. mortality and intraventricular haemorrhage) was low because of lack of precision with wide CIs. AUTHORS' CONCLUSIONS: The results from one study with wide CIs for magnitude of effect do not provide evidence either for or against the use of respiratory support before clamping the umbilical cord. A greater body of evidence is required as many of the outcomes of interest to the review occurred infrequently. Similarly, the one included study cannot answer the question of whether the intervention is or is not harmful.

Reduction in necrotizing enterocolitis and improved outcomes in preterm infants following routine supplementation with Lactobacillus GG in combination with bovine lactoferrin.

BACKGROUND: Preterm infants remain at high risk of adverse outcomes following necrotizing enterocolitis (NEC) and late onset sepsis (LOS). Meta-analysis of randomized trials has indicated a reduction in severe NEC following use of probiotics and bovine lactoferrin (LF). Overall, however, uncertainty remains over which probiotic, or combination to use. The aim of this study was to compare the incidence of severe NEC and LOS before and after routine supplementation with Lactobacillus GG (LGG) and LF. METHODS: In this retrospective cohort study, infants <32 weeks or <1500 g routinely received LGG and 100 mg lactoferrin daily from 2011 -2015 were compared with similar infants born from 2004-2008. Cases of NEC were Bell stage 2 or greater and LOS was blood or spinal fluid culture positive after 48 hrs of age. RESULTS: We noted a marked decline in the incidence of NEC from 3% to 1% with a RR of 0.29 (CI 0.1-0.9) and a number needed to benefit of 50. The cost of preventing one case of NEC was estimated to be NZ $2800, considerably lower than the cost of treatment. LOS rates were not significantly different. There was a decrease in retinopathy treatment rates. During the period there was one case of LGG sepsis in a 23 week gestation infant with abdominal pathology and one infant developed NEC after stopping prophylaxis. CONCLUSION: The rates of severe NEC was markedly reduced following prophylaxis. The case of LGG sepsis indicates caution is required in extremely preterm infants.

The Effects of Indirect- and Direct-Acting Anticoagulants on Lupus Anticoagulant Assays: A Large, Retrospective Study at a Coagulation Reference Laboratory.

OBJECTIVES: To investigate the effects of indirect- and direct-acting anticoagulants on the interpretation of lupus anticoagulant (LAC) assays. METHODS: A retrospective database review was performed to identify all LAC panels from November 2012 to November 2015. The positivity rates for three LAC tests were compared among various anticoagulant medications. RESULTS: This analysis included 7,721 LAC panels. Direct oral anticoagulants, warfarin, and unfractionated heparin (UFH) were associated with higher LAC positivity rates compared with patients not receiving documented anticoagulation (83% for argatroban, 58% for dabigatran, 72% for rivaroxaban, 53% for apixaban, 56% for warfarin, and 36% for UFH vs 29% for no anticoagulation, P < .025). Direct thrombin inhibitors mainly affected the activated partial thromboplastin time-based assays and the tissue thromboplastin inhibition index (TTI), while direct factor Xa inhibitors mainly affected the TTI and the dilute Russell viper venom ratio. CONCLUSIONS: Results of LAC testing performed while patients are receiving anticoagulant therapies should be interpreted with caution to avoid misdiagnosing patients with the antiphospholipid syndrome and potentially committing them to long-term anticoagulation therapy.

Hypothermia in Preterm Infants in the First Hours after Birth: Occurrence, Course and Risk Factors.

BACKGROUND: Hypothermia is associated with increased morbidity and mortality rates. Preterm infants frequently have hypothermia when they are admitted to the NICU, but there is no data on the occurrence of hypothermia during the first hours after admission. OBJECTIVE: To investigate the occurrence of hypothermia in preterm infants in the first three hours of admission and to identify risk factors. METHODS: Infants < 32 weeks of gestation included in a randomized trial with admission temperature as primary outcome were retrospectively analyzed for the occurrence of hypothermia (< 36.5°C) in the first three hours after admission. Risk factors were identified using linear regression analysis and logistic regression. RESULTS: In total 80 infants were included with a median (IQR) gestational age at birth of 29 (27-30) weeks. In 93% of the infants hypothermia occurred in the first three hours after admission. The median (IQR) duration of hypothermia was 101 (34-162) minutes, of which 24 (7-52) minutes the hypothermia was mild, 45 (4-111) minutes moderate, severe hypothermia hardly occurred. Gestational age and the occurrence of hypothermia at birth were independent risk factors for the occurrence of moderate and severe hypothermia and significantly correlated with duration of hypothermia. CONCLUSIONS: Hypothermia occurred often and for a long period in preterm infants in the first three hours of life, low gestational age and admission temperature were independent risk factors.