Improving the admission temperatures of preterm infants in the neonatal unit.

Use of plan-do-study-act cycles to increase the proportion of preterm infants born at <32 weeks' gestation admitted to a neonatal unit with a body temperature of 36.5-37.4°C.

In preterm infants, does fluid restriction, as opposed to liberal fluid prescription, reduce the risk of important morbidities and mortality?

AIM: To answer the clinical question: 'In preterm infants, does fluid restriction, as opposed to liberal fluid prescription, reduce the risk of important morbidities (namely, intraventricular haemorrhage, necrotising enterocolitis, bronchopulmonary dysplasia and patent ductus arteriosus) and mortality?' METHODS: Literature searches were conducted of Medline, Embase and Cochrane Library. Results were limited to human clinical trials on infants and those published in English. The reference lists of relevant articles were screened for further articles. Studies that examined measures which inform diagnostic criteria of morbidities of interest (such as echocardiographic changes) but did not go further to confirm or exclude presence of said morbidities in study populations were excluded. RESULTS: A total of 110 articles were found and screened by title and abstract. The final analysis included five randomised controlled trials and five case control studies. Among the randomised controlled trials, there is some suggestion (though not unanimous) that liberal fluid regimens are associated with an increased risk of patent ductus arteriosus, necrotising enterocolitis and mortality. Case control studies focused on patent ductus arteriosus and bronchopulmonary dysplasia or chronic lung disease, with all but one study suggesting an increased risk of these complications with liberal fluid regimens. CONCLUSION: Further investigation is needed to clarify the optimal fluid regimen for preterm infants to ensure adequate hydration and nutrition without contributing to serious complications.

International, multicentre, observational study of fluid bolus therapy in neonates.

AIM: To assess the prevalence, types and indications for fluid bolus therapy in neonates with haemodynamic compromise. METHODS: This was a pragmatic, international, multicentre observational study in neonatal units across Australasia, Europe and North America with a predefined study period of 10-15 study days per participating neonatal unit between December 2015 and March 2017. Infants ≤28 days of age who received a fluid bolus for the management of haemodynamic compromise (≥10 mL/kg given at ≤6 h) were included. RESULTS: A total of 163 neonates received a bolus over 8479 eligible patient days in 41 neonatal units. Prevalence of fluid bolus therapy varied between centres from 0 to 28.6% of admitted neonates per day, with a pooled prevalence rate of 1.5% (95% confidence interval 1.1-1.9%). The most common fluid used was 0.9% sodium chloride (129/163; 79%), and the volume of fluid administered was most commonly 10 mL/kg (115/163; 71%) over a median of 30 min (interquartile range 20-60). The most frequent indications were hypotension (n = 56; 34%), poor perfusion (n = 20; 12%) and metabolic acidosis (n = 20; 12%). Minimal or no clinical improvement was reported by clinicians in 66 of 163 cases (40%). CONCLUSIONS: Wide international variations in types, indications and effects of fluid bolus administration in haemodynamically compromised neonates suggest uncertainty in the risk-benefit profile. This is likely to reflect the lack of robust evidence to support the efficacy of different fluid types, doses and appropriate indications. Together, these highlight a need for further clinically relevant studies.

A systematic review of transfusion-associated graft-versus-host disease.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication of blood transfusion. The clinicolaboratory features of TA-GVHD and the relative contributions of recipient and component factors remain poorly understood. We conducted a systematic review of TA-GVHD reports. The HLA relationship between donor and recipient was classified as D = 0 when no donor antigens were foreign to the recipient vs D ≥ 1 when ≥1 donor antigen disparity occurred. We identified 348 unique cases. Criteria for component irradiation were met in 48.9% of cases (34.5% immune-compromised, 14.4% related-donor), although nonirradiated components were transfused in the vast majority of these (97.6%). Components were typically whole blood and red cells. When reported, component storage duration was ≤10 days in 94%, and 23 (6.6%) were leukoreduced (10 bedside, 2 prestorage, and 11 unknown). Among 84 cases with HLA data available, the category of D = 0 was present in 60 patients (71%) at either HLA class I or II loci and was more common among recipients without traditional indications for component irradiation. These data challenge the historic emphasis on host immune defects in the pathogenesis of TA-GVHD. The dominant mechanism of TA-GVHD in both immunocompetent and compromised hosts is exposure to viable donor lymphocytes not recognized as foreign by, but able to respond against, the recipient.

Washed versus unwashed red blood cells for transfusion for the prevention of morbidity and mortality in preterm infants.

BACKGROUND: Infants born very preterm often receive multiple red blood cell (RBC) transfusions during their initial hospitalisation. However, there is an increasing awareness of potential adverse effects of RBC transfusions in this vulnerable patient population. Modification of RBCs prior to transfusion, through washing with 0.9% saline, may reduce these adverse effects and reduce the rate of significant morbidity and mortality for preterm infants and improve outcomes for this high-risk group. OBJECTIVES: To determine whether pre-transfusion washing of RBCs prevents morbidity and mortality in preterm infants. 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 7), MEDLINE via PubMed (31 July 2015), EMBASE (31 July 2015), and CINAHL (31 July 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, cluster randomised, and quasi-randomised controlled trials including preterm infants (less than 32 weeks gestation) or very low birth weight infants (less than 1500 g), or both, who received one or more washed packed RBC transfusions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of the trials. We identified four studies from the initial search. After further review of the full-text studies, we found one study meeting the selection criteria. MAIN RESULTS: We included a single study enrolling a total of 21 infants for analysis in this review and reported on all-cause mortality during hospital stay, length of initial neonatal intensive care unit (NICU) stay (days), and duration of mechanical ventilation (days). There was no significant difference in mortality between the washed versus the unwashed RBCs for transfusion groups (risk ratio 1.63, 95% confidence interval (CI) 0.28 to 9.36; risk difference 0.10, 95% CI -0.26 to 0.45). There was no significant difference in the length of initial NICU stay between the washed versus the unwashed RBCs for transfusion groups (mean difference (MD) 25 days, 95% CI -21.15 to 71.15) or the duration of mechanical ventilation between the washed versus the unwashed RBCs for transfusion groups (MD 9.60 days, 95% CI -1.90 to 21.10). AUTHORS' CONCLUSIONS: We identified a single small study. The results from this study show a high level of uncertainty, as the confidence intervals are consistent with both a large improvement or a serious harm caused by the intervention. Consequently, there is insufficient evidence to support or refute the use of washed RBCs to prevent the development of significant neonatal morbidities or mortality. Further clinical trials are required to assess the potential effects of pre-transfusion washing of RBCs for preterm or very low birth weight infants, or both, on short- and long-term outcomes.

Temporal changes in blood product usage in preterm neonates born at less than 30 weeks' gestation in Canada.

BACKGROUND: Knowledge of neonatal transfusion practices remains limited to local cohorts or survey-based studies. This study evaluated the pattern and temporal changes in the types and frequency of blood product use among preterm neonates born at less than 30 weeks' gestation in Canada. STUDY DESIGN AND METHODS: A retrospective cohort study of preterm neonates born at less than 30 weeks' gestation and admitted to participating neonatal intensive care units in the Canadian Neonatal Network from 2004 to 2012 was conducted to evaluate blood product usage. The temporal change in red blood cell (RBC) use was evaluated by dividing the study period into three epochs: 2004 to 2006, 2007 to 2009, and 2010 to 2012. RESULTS: Of 14,868 eligible neonates admitted to participating units in Canada during the overall study period, 8252 (56%) received RBCs, 2151 (15%) platelets, 1556 (11%) fresh-frozen plasma, 915 (6%) albumin, and 302 (2%) cryoprecipitate. Temporal evaluation over three epochs revealed a trend toward fewer RBC transfusions among neonates born at 26 to 29 weeks' gestation (p = <0.01-0.04) but use remained unchanged or increased for neonates born at 23 to 25 weeks' gestation (p = 0.02-0.54). CONCLUSION: Blood product use remains at a very high frequency in preterm neonates born at less than 30 weeks' gestation. Evolutionary practice changes and relative high tolerance for anemia may be associated with a reduction in RBC usage in recent years in neonates born at at least 26 weeks' gestation. This contrasts with the ongoing higher usage of blood products observed at extremely low gestational ages.

Coinfusion of dextrose-containing fluids and red blood cells does not adversely affect in vitro red blood cell quality.

BACKGROUND: Transfusion guidelines advise against coinfusing red blood cells (RBCs) with solutions other than 0.9% saline. We evaluated the impact of coinfusion with dextrose-containing fluids (DW) on markers of RBC quality. STUDY DESIGN AND METHODS: A pool-and-split design was used to allow conditions to be tested on each pool within 2 hours of irradiation. Three pools at each storage age (5, 14, and 21 days) were created for each phase. In Phase 1, samples were infused through a neonatal transfusion apparatus alone or with treatment solutions: D5W, D10W, D5W/0.2% saline, and 0.9% saline. In Phase 2, samples were incubated alone or in a 1:1 ratio with treatment solutions and tested after 5, 30, and 180 minutes. Hemolysis, supernatant potassium, RBC indices, morphology, and deformability were measured on all samples. RESULTS: In Phase 1, RBCs transfused alone through the apparatus had higher (p<0.01) hematocrit, total hemoglobin, and supernatant potassium compared to all other groups. No statistical differences were identified between groups for other measured variables. In Phase 2, mean corpuscular volume of all samples containing DW increased with incubation length and were higher (p<0.01) than RBCs incubated alone or with 0.9% saline after 30 and 180 minutes. RBCs incubated with D5W and D5W/0.2% saline had greater (p<0.05) hemolysis than RBCs alone after 180 minutes. CONCLUSION: In vitro characteristics of RBCs coinfused with 0.9% saline or D10W were not adversely impacted. When developing clinical studies in neonates, we recommend use of D10W and a transfusion apparatus that minimizes the contact volume of the coinfusate with the RBC.

Plasma cytokines and markers of endothelial activation increase after packed red blood cell transfusion in the preterm infant.

BACKGROUND: Transfusion of packed red blood cells (PRBCs) saves lives in the neonatal critical care setting and is one of the most common interventions in the preterm infant. The number and volume of PRBC transfusions are associated with several major neonatal morbidities, although a direct causal link between transfusion and major neonatal morbidity is still to be proven. Transfusion-related immunomodulation (TRIM) may underlie these adverse outcomes, yet it has received little attention in the high-risk preterm infant. METHODS: One transfusion event was studied in infants ≤28 wk gestation between 2 and 6 wk postnatal age (n = 28). Plasma inflammatory cytokines and markers of endothelial activation were measured in the infants before and 2-4 h after transfusion, as well as in the donor pack. RESULTS: Median (range) age at transfusion was 18 (14-39) days with the pretransfusion hemoglobin level at 9.8 (7.4-10.2) g/dl. Interleukin (IL)-1ß (P = 0.01), IL-8 (P = <0.001), tumor necrosis factor-α (P = 0.008), and monocyte chemoattractant protein (P = 0.01) were increased after transfusion. A similar elevation in markers of endothelial activation was seen after transfusion with increased plasma macrophage inhibitory factor (P = 0.005) and soluble intracellular adhesion molecule-1 (P = <0.001). CONCLUSION: Production of inflammatory cytokines and immunoactivation of the endothelium observed after the transfusion of PRBCs in the preterm infant may be a manifestation of TRIM. The implications of this emerging phenomenon within the preterm neonatal population warrant further investigation.

Should intravenous immunoglobulin be used in infants with isoimmune haemolytic disease due to ABO incompatibility?

The use of intravenous immunoglobulin in isoimmune haemolytic disease due to ABO incompatibility is recommended by the American Academy of Pediatrics and the National Blood Authority, Australia. However, the evidence these recommendations are based on appears limited and, in some instances, outdated. In our article, we review the current available literature to help answer the question, 'In infants with isoimmune haemolytic disease due to ABO incompatibility [P], does use of intravenous immunoglobulin and intensive phototherapy [I] compared with intensive phototherapy alone [C] provide any clinically important benefits [O]?'

Longitudinal trends in domperidone dispensing to mothers of very preterm infants and its association with breast milk feeding at infant discharge: a retrospective study.

OBJECTIVE: This study aims: (a) to evaluate patterns of domperidone dispensing to mothers of very preterm (<32 weeks gestation) infants born before and after 2014 when international recommendations were made to limit its use and (b) to examine characteristics associated with domperidone dispensing and impacts on breast milk feeding rates at infant hospital discharge. DESIGN: Retrospective audit using linked electronic medical records and hospital pharmacy records. SETTING: Tertiary-referral neonatal intensive care unit at the Women's and Children's Hospital in South Australia. PATIENTS: Mothers of preterm infants admitted to neonatal intensive care from January 2004 to December 2018. MAIN OUTCOME MEASURES: Rate of domperidone dispensing compared pre-2014 and post-2014 recommendations using interrupted time series analyses, and breast milk feeding rates at infant discharge based on domperidone treatment status, adjusted for other factors known to influence breast milk production. RESULTS: Overall, domperidone was dispensed to 691 (41%) of 1688 mothers. Prior to 2014 recommendations, the proportion of women dispensed domperidone was stable. Following the recommendations, there was a significant reduction in trend (-2.55% per half year, 95% CI -4.57% to -0.53%;), reflecting less domperidone dispensing.Breast milk feeding rates at discharge remained consistently lower in infants of women dispensed domperidone than those who were not (adjusted OR 0.58, 95% CI 0.45 to 0.75). CONCLUSION: Domperidone dispensing in mothers of hospitalised very preterm infants has declined over time following international regulatory warnings. Breast milk feeding rates remain lower in mothers prescribed domperidone, suggesting further research is needed to optimise lactation support for mothers of very preterm infants.

Antenatal magnesium sulfate to prevent cerebral palsy.

Magnesium sulfate given to women before birth at <30 weeks' gestation reduces the risk of cerebral palsy in their children. Our study aimed to assess the impact of a local quality improvement programme, primarily using plan-do-study-act cycles, to increase the use of antenatal magnesium sulfate. After implementing our quality improvement programme, an average of 86% of babies delivered at <30 weeks' gestation were exposed to antenatal magnesium sulfate compared with a historical baseline rate of 63%. Our study strengthens the case for embedding quality improvement programmes in maternal perinatal care to reduce the impact of cerebral palsy on families and society.

Knowledge of Galactagogue Use During Breastfeeding in Australia: A Cross Sectional Online Survey.

BACKGROUND: Galactagogues have been used for centuries to induce, maintain, or increase a mother's milk supply. Recently, there has been an apparent increase in utilization and promotion of galactagogues, largely in the absence of data regarding their efficacy and safety. However, there is limited contemporary evidence about knowledge of these substances in the community or how and where individuals seek information. RESEARCH AIM: To evaluate knowledge about galactagogue use during breastfeeding among birth parents, including recognition of specific substances, perceptions of safety, and common information sources. METHOD: An online, prospective, cross-sectional survey of Australian birthing parents (N = 2055) who were currently breastfeeding or had previously breastfed their infants was conducted from September to December 2019. The survey included questions about recognition of galactagogues, perceptions of safety, and information-seeking behaviors. RESULTS: Among participants, 47% (n = 882) were primiparous and 65% (n = 1,219) were currently breastfeeding. The most recognized galactagogues included lactation cookies (89%; n = 1,828), brewer's yeast (79%; n = 1,629), fenugreek (74%; n = 1,519), and domperidone (69%; n = 1,420). Respondents cited the internet (52%; n = 1,066), lactation support providers (46%; n = 951), midwives (42%; n = 873), general practitioners (39%; n = 802), and social media (35%; n = 714) as common information sources. Lactation support providers and breastfeeding helplines were commonly rated as helpful; whereas, general practitioners and community pharmacists were often rated as unhelpful. While most participants perceived galactagogues to be safe, herbal or dietary galactagogues were perceived to be safer than pharmaceutical galactagogues. CONCLUSIONS: Our Australian community survey of individuals with current or previous breastfeeding experience identified widespread recognition of galactagogue use, with participants reporting a broad range of information-seeking behaviors and generally perceiving galactagogues as being safe to use.

A Quality Improvement Initiative to Reduce Blood Culture Contamination in the Neonatal Unit.

Peripheral blood culture contamination (BCC) can lead to an initiation of unnecessary antimicrobial treatment, further laboratory tests, increased length of stay, and increased costs. This study describes a 12-month quality improvement (QI) program to reduce the BCC rate in a neonatal unit by 50%. METHODS: The QI team focused on standardizing processes to align with best practices using process mapping and cause and effect diagrams. Plan-Do-Study-Act (PDSA) 1: inoculation of blood culture bottles with the introduction of transfer device; PDSA 2: preparation of the skin for peripheral intravenous cannula insertion; PDSA 3: aseptic technique education package; and PDSA 4: optimizing blood volume of blood collected for culture. The team used statistical process control methodology to detect special cause variation. RESULTS: Compliance with the standard processes as part of PSDA 1 improved from a mean level of 50% to 100% and for PDSA 2 improved from a mean level of 50% to 95%. After implementation of PDSA 3, scores on a relevant knowledge test increased from a mean of 39% (pretraining test; n = 10) to 92% (posttraining test; n = 10) (P < 0.001). Postimplementation of the processes for PDSA 4, a minimum of 1 mL was collected in 94% of blood culture collection events (n = 450) (mean 1.1 mL; range 0.5-3.5 mL). Special cause variation occurred after the implementation of the PDSA cycles. During the baseline period, the BCC rate was 2.0% and decreased to 1.0% postinterventions implementation. CONCLUSIONS: Interventions focused on standardizing practices around collection of blood cultures in neonates were associated with fewer contaminants.This study is reported according to the SQUIRE 2.0 guidelines.

Safety and efficacy of human milk-based fortifier in enterally fed preterm and/or low birthweight infants: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of the efficacy and safety of fortification of human milk with human milk-based fortifier versus cow's milk-based fortifier for use in preterm and/or very low birthweight infants. DESIGN: Randomised or quasi-randomised controlled trials comparing the effect of human milk fortification with human milk-based milk fortifier versus cow's milk-based fortifier in infants born <34 weeks' gestation and/or with birth weight <1500 g were identified by searching databases, clinical trial registries and reference lists until 5 November 2019. Two authors independently extracted data and assessed evidence quality. Meta-analyses were conducted using fixed or random effects models, as appropriate. MAIN OUTCOME MEASURES: Necrotising enterocolitis (Bell's stage II or higher) and late-onset sepsis. RESULTS: Of 863 unique records identified, 16 full-text trials were screened and 2 trials involving 334 infants were included. Primary outcome data were available for 332 infants. Use of human milk-based fortifier compared with cow's milk-based fortifier reduced the risk of necrotising enterocolitis (risk ratio 0.47, 95% CI 0.22 to 0.98). There was no clear evidence of an effect on late-onset sepsis or any other outcomes. The quality of evidence was low to very low due to imprecision and lack of blinding in one study. CONCLUSIONS: Findings suggest that there is a reduction in the incidence of necrotising enterocolitis with human milk-based fortifiers compared with cow's milk-based fortifiers. The overall quality of evidence is low. Further appropriately powered trials are required before this intervention can be routinely recommended for preterm infants.

Tailoring Human Milk Oligosaccharides to Prevent Necrotising Enterocolitis Among Preterm Infants.

Necrotising enterocolitis (NEC) is a devastating disease affecting preterm infants, with little improvement in mortality rates and treatment strategies in the last 30 years. Human milk oligosaccharides (HMOs) are emerging as a potential preventive therapy, with multiple protective functions postulated. Our aim is to summarise the evidence concerning the role of HMOs in NEC development and emerging strategies to tailor the delivery of HMOs to preterm infants. Most research efforts to date have focused on supplementing preterm infants with simple oligosaccharides, which are structurally different to HMOs and derived mainly from plants. Clinical trials demonstrate limited benefits for NEC prevention arising from the use of these supplements. Alternative strategies under investigation include optimising HMOs for infants receiving donor human milk, concentrating oligosaccharides from donor human milk and from animal milks, as well as more sophisticated synthetic oligosaccharide production strategies. Critically, high quality evidence to support implementation of any of these approaches in the neonatal unit is lacking. Whether it is a specific HMO alone or a combination of HMOs that exert protective effects remains to be elucidated. Further challenges include how best to manufacture and administer oligosaccharides whilst retaining bioactivity and safety, including evaluation of the long-term effects of altering the balance of HMOs and gut microbiota in preterm infants. While several human clinical trials are underway, further research is needed to understand whether a tailored approach to oligosaccharide supplementation is beneficial for preterm infants.

Use and experiences of galactagogues while breastfeeding among Australian women.

BACKGROUND: Galactagogues are substances thought to increase breast milk production, however evidence to support their efficacy and safety remain limited. We undertook a survey among Australian women to examine patterns of use of galactagogues and perceptions regarding their safety and effectiveness. METHODS: An online, cross-sectional survey was distributed between September and December 2019 via national breastfeeding and preterm birth support organisations, and networks of several research institutions in Australia. Women were eligible to participate if they lived in Australia and were currently/previously breastfeeding. The survey included questions about galactagogue use (including duration and timing), side effects and perceived effectiveness (on a scale of 1 [Not at all effective] to 5 [Extremely effective]). RESULTS: Among 1876 respondents, 1120 (60%) reported using one or more galactagogues. Women were 31.5 ± 4.8 years (mean ± standard deviation) at their most recent birth. Sixty-five percent of women were currently breastfeeding at the time of the survey. The most commonly reported galactagogues included lactation cookies (47%), brewer's yeast (32%), fenugreek (22%) and domperidone (19%). The mean duration of use for each galactagogue ranged from 2 to 20 weeks. Approximately 1 in 6 women reported commencing galactagogues within the first week postpartum. Most women reported receiving recommendations to use herbal/dietary galactagogues from the internet (38%) or friends (25%), whereas pharmaceutical galactagogues were most commonly prescribed by General Practitioners (72%). The perceived effectiveness varied greatly across galactagogues. Perceived effectiveness was highest for domperidone (mean rating of 3.3 compared with 2.0 to 3.0 among other galactagogues). Over 23% of domperidone users reported experiencing multiple side effects, compared to an average of 3% of women taking herbal galactagogues. CONCLUSIONS: This survey demonstrates that galactagogues use is common in Australia. Further research is needed to generate robust evidence about galactagogues' efficacy and safety to support evidence-based strategies and improve breastfeeding outcomes.

Fluid Therapy: Friend or Foe?

Many questions surround fluid bolus therapy and subsequent fluid management in neonatal critical care as they do in pediatric and adult critical care. This review explores the known key clinical aspects of fluid bolus therapy and fluid balance in the first 7 days of life and provides suggestions for further work in this area. It draws on the pediatric and adult critical care literature to provide thought-provoking data around the potential harms of excessive intravenous fluids, which may prove relevant to neonatology. Current data suggest that fluid bolus therapy and early-life positive fluid balance in neonates may be associated with harm.