Reducing intravenous antibiotics in neonates born ≥35 weeks' gestation: A quality improvement study.

AIM: To assess the impact of the Early Onset Sepsis (EOS) calculator, implemented as a quality improvement study, to reduce the rate of unnecessary antibiotics in neonates born ≥35 weeks' gestation. METHODS: An audit of routinely collected hospital data from January 2008 to March 2014 (retrospective) and from January 2018 to September 2019 (prospective) determined baseline incidence of EOS intravenous antibiotic use in neonates born ≥35 weeks' gestation in a tertiary level perinatal centre. Plan-do-study-act (PDSA) cycles were applied to implement the EOS calculator. Statistical process control methodology and time series analysis assessments were used to assess the potential impact of the PDSA cycles on the rate of intravenous antibiotics, blood culture collection, EOS, length of stay and health care costs (not adjusted for potential confounders). RESULTS: In the study population, from January 2008 to March 2014, the baseline incidence of intravenous antibiotic use was 10.49% (2970/28290), whilst only 0.067% (19/28290) neonates had culture proven EOS. From January 2018 to October 2019, prior to implementation of the EOS calculator, 13.3% (1119/8411) neonates were treated with intravenous antibiotic and the use decreased to 8.3% (61/734) post-implementation. The rate of blood culture collection decreased from 14.4% (1211/8411) to 11.9% (87/734). There were no cases of missed EOS. Length of stay decreased from 2.68 to 2.39 days, with an estimated cost saving of $366 per patient per admission. CONCLUSION: Implementing the EOS calculator in a tertiary hospital setting reduced invasive investigations for EOS and intravenous antibiotic use among neonates ≥35 weeks' gestation. This can result in reduced length of neonatal hospital stays, and associated health care cost savings and may reduce separation of mother and baby.

Thresholds for Red Blood Cell Transfusion in Preterm Infants: Evidence to Practice.

Rapid blood loss with circulatory shock is dangerous for the preterm infant as cardiac output and oxygen-carrying capacity are simultaneously imperilled. This requires prompt restoration of circulating blood volume with emergency transfusion. It is recommended that clinicians use both clinical and laboratory responses to guide transfusion requirements in this situation. For preterm infants with anemia of prematurity, it is recommended that clinicians use a restrictive algorithm from one of two recently published clinical trials. Transfusion outside these algorithms in very preterm infants is not evidence-based and is actively discouraged.

Study protocol of the WashT Trial: transfusion with washed versus unwashed red blood cells to reduce morbidity and mortality in infants born less than 28 weeks' gestation - a multicentre, blinded, parallel group, randomised controlled trial.

INTRODUCTION: Many extremely preterm newborns develop anaemia requiring a transfusion, with most receiving three to five transfusions during their admission. While transfusions save lives, the potential for transfusion-related adverse outcomes is an area of growing concern. Transfusion is an independent predictor of death and is associated with increased morbidity, length of hospital stay, risk of infection and immune modulation. The underlying mechanisms include adverse pro-inflammatory and immunosuppressive responses. Evidence supports an association between transfusion of washed red cells and fewer post-transfusion complications potentially through removal of chemokines, lipids, microaggregates and other biological response modifiers. However, the clinical and cost-effectiveness of washed cells have not been determined. METHODS AND ANALYSIS: This is a multicentre, randomised, double-blinded trial of washed versus unwashed red cells. Infants <28 weeks' gestation requiring a transfusion will be enrolled. Transfusion approaches will be standardised within each study centre and will occur as soon as possible with a recommended fixed transfusion volume of 15 mL/kg whenever the haemoglobin is equal to or falls below a predefined restrictive threshold, or when clinically indicated. The primary outcome is a composite of mortality and/or major morbidity to first discharge home, defined as one or more of the following: physiologically defined bronchopulmonary dysplasia; unilateral or bilateral retinopathy of prematurity grade >2, and; necrotising enterocolitis stage ≥2. To detect a 10% absolute reduction in the composite outcome from 69% with unwashed red blood cell (RBCs) to 59% with washed RBCs with 90% power, requires a sample size of 1124 infants (562 per group). Analyses will be performed on an intention-to-treat basis with a prespecified statistical analysis plan. A cost-effectiveness analysis will also be undertaken. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Women's and Children's Health Network Human Research Ethics Committee (HREC/12/WCHN/55). The study findings will be disseminated through peer-reviewed articles and conferences. TRIAL REGISTRATION NUMBER: ACTRN12613000237785 Australian New Zealand Clinical Trials Registry.

Does donor sex influence the potential for transfusion with washed packed red blood cells to limit transfusion-related immune responses in preterm newborns?

OBJECTIVE: To evaluate the association of donor sex with transfusion-associated recipient immune responses in preterm newborns receiving unwashed and washed blood. DESIGN: A cohort study using data collected during the Effect of Washed versus Unwashed Packed Red Blood Cell Transfusion on Immune Responses in the Extremely Preterm Newborn randomised trial. SETTING: Participants were recruited from two South Australian hospitals between September 2015 and December 2020. PATIENTS: Preterm newborns (<29 weeks). INTERVENTIONS: Transfusion with unwashed and washed packed red blood cells (PRBCs) from either exclusively male or any female donor for the first three transfusions. MAIN OUTCOMES MEASURES: The primary outcome was the change from baseline in post-transfusion plasma cytokine concentrations, specifically interferon gamma, interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, IL-17A and tumour necrosis factor (TNF). RESULTS: In total, 153 newborns were evaluated. By the third transfusion, the magnitude of pretransfusion to post-transfusion change in cytokines between the groups differed for IL-6 (p=0.003), IL-12 (p=0.008), IL-17A (p=0.003) and TNF (p=0.007). On post hoc comparison, compared with the unwashed-any female donor group, IL-6 (p<0.05), IL-12 (p<0.05) and IL-17A (p<0.01) were lower in the washed-exclusively male donor group, and IL-6 (p<0.01), IL-12 (p<0.05) and TNF (p<0.01) were lower in the washed-any female donor group. CONCLUSION: These findings suggest that transfusion with unwashed PRBCs from female donors is associated with an increased recipient immune response, an effect that can be ameliorated with pretransfusion washing. Larger randomised controlled studies confirming this mechanistic link between donor sex and transfusion-associated morbidity are warranted. TRIAL REGISTRATION NUMBER: ACTRN12613000237785.

Red Blood Cell Donor Sex Associated Effects on Morbidity and Mortality in the Extremely Preterm Newborn.

Transfusion exposure increases the risk of death in critically ill patients of all ages. This was thought to relate to co-morbidities in the transfusion recipient. However, donor characteristics are increasingly recognised as critical to transfusion recipient outcome with systematic reviews suggesting blood donor sex influences transfusion recipient health. Originally focusing on plasma and platelet transfusions, retrospective studies report greater risks of adverse outcomes such as transfusion related acute lung injury in those receiving products from female donors. There is increasing awareness that exposure to red blood cells (RBCs) poses a similar risk. Recent studies focusing on transfusion related outcomes in extremely preterm newborns report conflicting data on the association between blood donor sex and outcomes. Despite a renewed focus on lower versus higher transfusion thresholds in neonatal clinical practice, this group remain a heavily transfused population, receiving on average 3-5 RBC transfusions during their primary hospital admission. Therefore, evidence supporting a role for better donor selection could have a significant impact on clinical outcomes in this high-risk population. Here, we review the emerging evidence for an association between blood donor sex and clinical outcomes in extremely preterm newborns receiving one or more transfusions.

Differential effects of ibuprofen and indomethacin on cerebral oxygen kinetics in the very preterm baby.

Background: Ibuprofen is preferred to indomethacin for treatment of a significant patent ductus arteriosus (PDA) in preterm babies despite indomethacin being associated with a lower risk of intraventricular haemorrhage. This difference is thought to relate to the discrepant effects of each medication on cerebral oxygen kinetics yet the effect of ibuprofen on cerebral perfusion is uncertain. Methods: Forty-eight babies < 30 weeks with a significant PDA, defined by echocardiography, were randomly assigned to either indomethacin or ibuprofen (n = 24 per group) and stratified by gestation and chronologic age. Cerebral blood flow [total internal carotid blood flow (TICF)] and oxygen physiology [oxygen delivery (modCerbDO2) and consumption (modCerbVO2)] were measured using cranial Doppler ultrasound and near-infrared spectroscopy, and cerebral oxygen extraction (cFTOE) calculated, immediately before and following administration. Temporal and treatment related changes were analysed. Results: A fixed effect of time was seen for TICF (p = 0.03) and therefore modCerbDO2 (p = 0.046) and cFTOE (p = 0.04) for indomethacin alone. In the indomethacin group, TICF and modCerbDO2 fell from baseline to 5 and 30 min respectively (TICF p < 0.01, cDO2 p = 0.01) before increasing from 5 min to 24 h (p < 0.01) and 30 min and 24 h (p < 0.01) timepoints. cFTOE peaked at 30 min (p = 0.02) returning to baseline at 24 h. There was a parallel increase in arterial lactate. Conclusion: Indomethacin significantly reduces cerebral blood flow soon after administration, resulting in a parallel increase in oxygen extraction and arterial lactate. This implies that the balance of oxygen kinetics at the time of treatment may be critical in very preterm babies with significant PDA.

Placental pathology of resuscitated apparent stillbirth.

Resuscitated apparent stillbirth (RAS) is defined as an infant with APGAR scores of 0 at 1 minute of life who receives successful resuscitation. Assessment of placental pathology is considered standard of care in such infants, but the clinical significance of these placental findings as they relate to clinical outcomes has yet to be described within the literature. We report the findings of a retrospective study of placental pathology as defined by the Amsterdam and Dublin criteria of RAS infants born in South Australia over an 8-year period. The aim of this study was to assess whether placental pathology was able to predict RAS clinical outcomes of death, survival with adverse neurological outcomes, and survival with normal neurological outcomes. The RAS cohort within our study is small, reflecting the low incidence of RAS. Of the 25 RAS subjects 16 survived, five with abnormal neurological outcomes and 11 with normal neurological outcomes. No statistically significant difference was seen between the clinical outcome groups in the incidence of specific macroscopic and microscopic placental findings. No sentinel lesion was seen in any one clinical outcome group. Relevant placental pathology was found in all but one subject validating the role of placental pathology in determination of the aetiology of RAS. The most common finding was maternal vascular malperfusion. Placental pathology in RAS infants remains relevant but is unable to contribute to the matrix of predictive information available to the clinician and family.

Effect of washed versus unwashed red blood cells on transfusion-related immune responses in preterm newborns.

Objectives: Transfusion with washed packed red blood cells (PRBCs) may be associated with reduced transfusion-related pro-inflammatory cytokine production. This may be because of alterations in recipient immune responses. Methods: This randomised trial evaluated the effect of transfusion with washed compared with unwashed PRBCs on pro-inflammatory cytokines and endothelial activation in 154 preterm newborns born before 29 weeks' gestation. Changes in plasma cytokines and measures of endothelial activation in recipient blood were analysed after each of the first three transfusions. Results: By the third transfusion, infants receiving unwashed blood had an increase in IL-17A (P = 0.04) and TNF (P = 0.007), whereas infants receiving washed blood had reductions in IL-17A (P = 0.013), TNF (P = 0.048), IL-6 (P = 0.001), IL-8 (P = 0.037), IL-12 (P = 0.001) and IFN-γ (P = 0.001). The magnitude of the post-transfusion increase in cytokines did not change between the first and third transfusions in the unwashed group but decreased in the washed group for IL-12 (P = 0.001), IL-17A (P = 0.01) and TNF (P = 0.03), with the difference between the groups reaching significance by the third transfusion (P < 0.001 for each cytokine). Conclusion: The pro-inflammatory immune response to transfusion in preterm infants can be modified when PRBCs are washed prior to transfusion. Further studies are required to determine whether the use of washed PRBCs for neonatal transfusion translates into reduced morbidity and mortality.

Non-invasively Measured Venous Oxygen Saturation as Early Marker of Impaired Oxygen Delivery in Preterm Neonates.

INTRODUCTION: Adequate oxygen supply for preterm neonates may be defined through non-invasive measurement of venous oxygen saturation (SvO2) and fractional oxygen extraction using near-infrared spectroscopy (NIRS). We investigated whether there was a difference in peripheral muscle SvO2 (pSvO2) and peripheral fractional oxygen extraction (pFOE) in preterm neonates with early inflammation/infection compared to healthy subjects during the first 72 h after birth. MATERIALS AND METHODS: We retrospectively analyzed secondary outcome parameters of prospective observational studies, including preterm neonates at risk of infection in whom peripheral NIRS measurements were performed in combination with venous occlusions. Early neonatal inflammation/infection was diagnosed by clinical signs and laboratory parameters. Peripheral muscle tissue oxygenation index (pTOI) was measured using either NIRO 300 or NIRO 200-NX (both Hamamatsu Photonics, Japan) on the patients' lower legs. Using 20-s venous occlusions, pSvO2 and pFOE were calculated incorporating simultaneous measurements of arterial oxygen saturation (SpO2). RESULTS: We analyzed measurements from 226 preterm neonates (median gestational age 33.9 weeks), 64 (28.3%) of whom were diagnosed with early neonatal inflammation/infection. During the first 24 h after birth, pSvO2 (66.9% [62.6-69.2] vs. 69.4% [64.6-72.0]; p = 0.04) and pTOI (68.6% [65.3-71.9] vs. 71.7% [67.3-75.1]; p = 0.02) were lower in those neonates with inflammation/infection, while there was no such difference for measurements between 24-48 and 48-72 h. DISCUSSION: NIRS measurement of pSvO2 and pFOE is feasible and may be utilized for early detection of impaired peripheral oxygen delivery. As pTOI was also significantly lower, this parameter may serve as substitute for diminished regional oxygen supply.

Supraglottic airway devices for administration of surfactant to newborn infants with respiratory distress syndrome: a narrative review.

Surfactant is an effective treatment for respiratory distress syndrome, being particularly important for infants in whom continuous positive airway pressure (CPAP) provides insufficient support. Supraglottic airway devices present an attractive option for surfactant delivery, particularly as an alternative to methods dependent on direct laryngoscopy, a procedural skill that is both difficult to learn and in which to maintain competence. Published studies provide encouraging data that surfactant administration by supraglottic airway device can be performed with a high rate of success and may reduce the need for subsequent intubation compared with either continued CPAP or surfactant administration via endotracheal tube. However, existing randomised controlled trials (RCTs) are heterogeneous in design and include just over 350 infants in total. To date, all RCT evidence has been generated in tertiary units, whereas the greatest potential for benefit from the use of these devices is likely to be in non-tertiary settings. Future research should investigate choice and utility of device in addition to safety and effectiveness of procedure. Importantly, studies conducted in non-tertiary settings should evaluate feasibility, meaningful clinical outcomes and the impact that this approach might have on infants and their families. Supraglottic airway devices may represent a simple and effective mode of surfactant administration that can be widely used by a variety of clinicians. However, further well-designed RCTs are required to determine their role, safety and effectiveness in both tertiary and non-tertiary settings before introduction into routine clinical practice.

Feasibility and accuracy of cord blood sampling for admission laboratory investigations: A pilot trial.

AIM: Phlebotomy losses greatly contribute to anaemia following preterm birth. Therefore, the possibility of drawing initial tests from the placenta seems attractive. There is a lack of literature regarding the feasibility and accuracy of pathology tests taken from umbilical arterial and venous (UAB/UVB) compared to blood collected from the newborn. METHODS: UAB and UVB complete blood pictures were compared with the initial neonatal blood test. The relationship between UAB, UVB and neonatal complete blood picture values was determined by Spearman's Rho correlation with absolute values compared by Kruskal-Wallis. P < 0.05 was considered significant. RESULTS: Neonatal haemoglobin, white cell count, immature/total ratio and platelets were significantly correlated to the corresponding values in the UAB and UVB (all P < 0.001). While UAB and UVB haemoglobin and white cell count were similar, both were significantly lower than the neonatal values (P < 0.001 and P = 0.014, respectively). No difference was seen for immature/total ratio and platelet concentrations. UVB blood culture (BC) was feasible (90%), even with delayed cord clamping, and the UVB BC volume was significantly higher (P < 0.001), with a low rate of BC contamination (1.5%). CONCLUSIONS: Our findings support the feasibility and accuracy of umbilical blood in place of blood collected from the newborn. This reduces the phlebotomy losses and allows higher blood volume collection which may increase the sensitivity of BC collection.

Effect of parenteral lipid emulsion on preterm infant PUFAs and their downstream metabolites.

OBJECTIVE: Oxylipins synthesized by oxidation of long-chain polyunsaturated fatty acids (LCPUFAs) are bioactive downstream lipid mediators. The aim of this study was to describe oxylipin levels in preterm infants born 30 to 33 weeks' gestation who were enrolled in a randomized controlled trial in which peripheral parenteral nutrition (P-PN), including lipid emulsion (containing soy, medium chain triglyceride, olive and fish oil), was compared with 10% glucose on growth during the transition to enteral feeds. METHODS: Of the 92 infants randomized to the P-PN study, the first 72 (P-PN n = 34, control n = 38) had blood taken for fatty acid analyses. P-PN infants received parenteral nutrition including 3% protein, 8% glucose and 17% SMOFlipid® lipid (containing soy, medium chain triglyceride, olive and fish oil), and control infants 10% glucose. Both groups commenced enteral feeds when clinically stable. 32 oxylipins and 5 free fatty acids were screened (using ultra-high-performance liquid chromatography-tandem mass spectrometry), and 5 total LCPUFA were measured (using gas chromatography), on study days 1 (baseline), 2, 4, 7, 14 and 21. RESULTS: Both total and free LA, ALA and EPA were significantly higher in the P-PN group compared with control over the first week of life. Whereas total AA was significantly lower and free DHA significantly higher over the same time period. All LA, ALA, EPA and four DHA derived oxylipins detected were significantly higher in the P-PN group compared with the control group during the first week of life, with three AA derived oxylipins significantly lower and one significantly higher. CONCLUSIONS: Parenteral lipid emulsion resulted in a change in total and free fatty acids and related oxylipins with the profiles suggesting increased omega-6 driven inflammation. Further studies to investigate the association between the oxylipin levels and nutrition and to determine whether the oxylipin profiles influence the clinical outcome in preterm infants are warranted.

The efficacy and safety of peripheral intravenous parenteral nutrition vs 10% glucose in preterm infants born 30 to 33 weeks' gestation: a randomised controlled trial.

BACKGROUND: Preterm infants born 30 to 33 weeks' gestation often require early support with intravenous fluids because of respiratory distress, hypoglycemia or feed intolerance. When full feeds are anticipated to be reached within the first week, risks associated with intravenous delivery mode and type must be carefully considered. Recommendations are for parenteral nutrition to be infused via central venous lines (because of the high osmolarity), however, given the risks associated with central lines, clinicians may opt for 10% glucose via peripheral venous catheter when the need is short-term. We therefore compare a low osmolarity peripheral intravenous parenteral nutrition (P-PN) solution with peripheral intravenous 10% glucose on growth rate in preterm infants born 30 to 33 weeks' gestation. METHODS: In this parallel group, single centre, superiority, non-blinded, randomised controlled trial, 92 (P-PN 42, control 50) infants born 30+ 0 to 33+ 6 weeks' gestation, were randomised within 24 h of age, to receive either P-PN (8% glucose, 30 g/L amino acids, 500 IU/L heparin and SMOFlipid®) or a control of peripheral intravenous 10% glucose. Both groups received enteral feeds according to hospital protocol. The primary outcome was rate of weight gain from birth to 21 days of age. RESULTS: The rate of weight gain was significantly increased in P-PN infants compared with control (P-PN, n = 42, 18.7, SD 6.6 g/d vs control, n = 50, 14.8, SD 6.0 g/d; adjusted mean difference 3.9 g/d, 95% CI 1.3 to 6.6; P = 0.004), with the effect maintained to discharge home. Days to regain birthweight were significantly reduced and length gain significantly increased in P-PN infants. One infant in the P-PN group had a stage 3 extravasation which rapidly resolved. Blood urea nitrogen and triglyceride levels were significantly higher in the P-PN group in the first week of life, but there were no instances of abnormally high levels. There were no significant differences in any other clinical or biochemical outcomes. CONCLUSION: P-PN improves the rate of weight gain to discharge home in preterm infants born 30 to 33 weeks gestation compared with peripheral intravenous 10% glucose. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000925448 . Registered 12 July 2016.

Effect of repeat transfusion exposure on plasma cytokine and markers of endothelial activation in the extremely preterm neonate.

BACKGROUND: Very preterm newborns receive up to three to five red blood cell (RBC) transfusions, often early, after birth. Despite awareness of the association of transfusion with increases in cytokines and markers of endothelial activation, research has focused on single transfusions weeks after birth. With pathophysiologic processes contributing to the development of morbidities starting soon after delivery, we investigated the response to early, repeated transfusion exposure. STUDY DESIGN AND METHODS: Three consecutive transfusion exposures were studied in transfusion-naive infants less than 30 weeks' gestation (n = 46). Plasma cytokines and markers of endothelial activation were measured before and 2 to 4 hours after transfusion by multiplex enzyme-linked immunosorbent assay. RESULTS: The median (IQR) age was 3 (1-9) days at first transfusion, 7 (3-20) days at the second, and 18 (7-28) days at the third. Baseline concentrations did not differ between the three transfusions. Interleukin (IL)-17A and tumor necrosis factor (TNF)-α did not change after the first transfusion but increased after the second (P < .05) and third transfusions (P < .01). While IL-1ß, IL-6, and IL-8 concentrations did not differ after the first and second transfusions, all increased after the third (IL-1ß, P < .01; IL-6, P < .01; IL-8, P < .05). The magnitude of posttransfusion increase in IL-1ß, IL-17A, and TNF-α increased between the first and third transfusion exposure. CONCLUSION: Early, repeated transfusion results in alterations in proinflammatory cytokines and markers of endothelial activation in the very preterm newborn and suggests that the potential for transfusion-related immunomodulation is present in the initial days after birth rather than confined to later in the postnatal period.

Standardised neonatal parenteral nutrition formulations - Australasian neonatal parenteral nutrition consensus update 2017.

BACKGROUND: The first consensus standardised neonatal parenteral nutrition formulations were implemented in many neonatal units in Australia in 2012. The current update involving 49 units from Australia, New Zealand, Singapore, Malaysia and India was conducted between September 2015 and December 2017 with the aim to review and update the 2012 formulations and guidelines. METHODS: A systematic review of available evidence for each parenteral nutrient was undertaken and new standardised formulations and guidelines were developed. RESULTS: Five existing preterm Amino acid-Dextrose formulations have been modified and two new concentrated Amino acid-Dextrose formulations added to optimise amino acid and nutrient intake according to gestation. Organic phosphate has replaced inorganic phosphate allowing for an increase in calcium and phosphate content, and acetate reduced. Lipid emulsions are unchanged, with both SMOFlipid (Fresenius Kabi, Australia) and ClinOleic (Baxter Healthcare, Australia) preparations included. The physicochemical compatibility and stability of all formulations have been tested and confirmed. Guidelines to standardise the parenteral nutrition clinical practice across facilities have also been developed. CONCLUSIONS: The 2017 PN formulations and guidelines developed by the 2017 Neonatal Parenteral Nutrition Consensus Group offer concise and practical instructions to clinicians on how to implement current and up-to-date evidence based PN to the NICU population.

Intravenous fat induces changes in PUFA and their bioactive metabolites: Comparison between Japanese and Australian preterm infants.

OBJECTIVE: Oxylipins are biologically active signaling molecules that initiate and resolve inflammation; they are synthesized by oxidation of polyunsaturated fatty acids (PUFAs) and reflect PUFA intake and status. The PUFA intake in preterm infants differs between countries because of the type of lipid emulsions used and the PUFA content of breast milk. We compared total blood PUFA, free PUFA and their oxylipin levels in dried whole blood samples from preterm infants born in Australia and Japan. METHODS: We enrolled 30 and 14 preterm infants born less than 31 weeks' gestation, from Adelaide and Japan respectively. Blood samples were obtained from cord blood, and on postnatal days 4, 7, 14 and 28. Total PUFAs were measured using gas chromatography, while free fatty acids and oxylipins were screened using ultra high-performance liquid chromatography mass spectroscopy. RESULTS: Differences in the levels of blood PUFA between the centres were found which were in line with the timing and type of lipid emulsion administration. Significant differences in longitudinal levels were seen more often in free PUFA and their oxylipins than in total blood PUFA. This was particularly true for AA and DHA. In contrast, differences in the levels could be seen in total blood EPA, as well as in free EPA and its oxylipins. Further, levels of many free PUFA and their oxylipins were higher in Japanese infants than in Australian infants. CONCLUSION: Differences in total and free fatty acids and unesterified oxylipins, were observed during the first weeks of life and between preterm infants born in Australia and Japan, which were likely a reflection of the type of lipid emulsion and timing of administration. The clinical significance of these changes remains to be explored.

Patterns of placental antimicrobial resistance in preterm birth before 30 completed weeks gestation complicated by preterm prelabour rupture of membranes.

BACKGROUND: While many guidelines recommend a 10-day course of oral erythromycin following preterm prelabour rupture of membranes (PPROM) as derived from the ORACLE I trial, evidence is emerging that this may encourage a state of antenatal genital tract dysbiosis. In addition, erythromycin's lack of efficacy toward Gram-negative microorganisms may promote colonisation and infection, conveying more significant unrecognised risk for very and extremely preterm newborns. AIMS: To define patterns of placental infection or colonisation in newborns born before 30 completed weeks gestation following PPROM. MATERIALS AND METHODS: Retrospective cohort study of mother-infant dyads who delivered at < 30 completed weeks gestation following PPROM in a South Australian tertiary perinatal centre between January 2012 and December 2015. Main outcome measures included placental and neonatal culture and sensitivities within 72 h of delivery and histologic chorioamnionitis. Categorical characteristics were analysed using two-sided Fisher's exact test and numerical characteristics via analysis of variance. RESULTS: During the four years studied, 126 infant-mother dyads were identified. Where a placental swab was taken, 23.9% cultured Gram-negative organisms and the majority (58.8%) were antimicrobial-resistant. Those that received erythromycin had increased incidence of antimicrobial-resistant Gram-negative organisms on placental swab (P = 0.02). All cases of neonatal early-onset sepsis (EOS), including two cases of multi-resistant Gram-negative EOS, occurred in those who received erythromycin. CONCLUSIONS: The current antibiotic recommendations for PPROM may promote selection of unhindered antimicrobial-resistant Gram-negative organisms and may increase risk of Gram-negative EOS in very and extremely preterm newborns. Further wide-scale examination of antibiotic recommendations in PPROM is necessary.

Maternal intramuscular dexamethasone versus betamethasone before preterm birth (ASTEROID): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Antenatal corticosteroids given to women before preterm birth improve infant survival and health. However, whether dexamethasone or betamethasone have better maternal, neonatal, and childhood health outcomes remains unclear. We therefore aimed to assess whether administration of antenatal dexamethasone to women at risk of preterm birth reduced the risk of death or neurosensory disability in their children at age 2 years compared with betamethasone. We also aimed to assess whether dexamethasone reduced neonatal morbidity, had benefits for the mother, or affected childhood body size, blood pressure, behaviour, or general health compared with betamethasone. METHODS: In this multicentre, double-blind, randomised controlled trial, we recruited pregnant women from 14 maternity hospitals in Australia and New Zealand that could provide care to preterm babies. Women were eligible for study inclusion if they were at risk of preterm birth before 34 weeks of gestation, had a singleton or twin pregnancy, and had no contraindications to antenatal corticosteroids. We randomly assigned women (1:1) to receive two intramuscular injections of either 12 mg dexamethasone (dexamethasone sodium phosphate) or 11·4 mg betamethasone (Celestone Chronodose), 24 h apart. The randomisation schedule used balanced, variable blocks that were stratified by hospital, gestational age, and number of fetuses (singleton or twins). We masked all participants, staff, and assessors to treatment groups. Analyses were by intention to treat. The primary outcome was death or neurosensory disability at age 2 years (corrected for prematurity). This study is registered with ANZCTR, ACTRN12608000631303. FINDINGS: Between Jan 28, 2009, and Feb 1, 2013, we randomly assigned 1346 (78%) women who were pregnant with 1509 fetuses to groups: 679 (50%) women were assigned to receive dexamethasone and 667 (50%) women were assigned to receive betamethasone. 27 (4%) fetuses, infants, or children in the dexamethasone group and 28 (4%) fetuses, infants, or children in the betamethasone group died before age 2 years. The primary outcome of death or neurosensory disability at age 2 years was determined for 603 (79%) of 763 fetuses whose mothers received dexamethasone and 591 (79%) of 746 fetuses whose mothers received betamethasone. We found a similar incidence of death or neurosensory disability in the dexamethasone (198 [33%] of 603 infants) and betamethasone groups (192 [32%] of 591 infants; adjusted relative risk [adjRR] 0·97, 95% CI 0·83 to 1·13; p=0·66). 18 (3%) of 679 women in the dexamethasone group and 28 of 667 (4%) women in the betamethasone group reported side-effects. Discomfort at the injection site, the most frequent side-effect, was less likely in the dexamethasone group than in the betamethasone group (six [1%] women vs 17 [3%] women; p=0·02). INTERPRETATION: The incidence of survival without neurosensory disability at age 2 years did not differ between dexamethasone and betamethasone treatment. Our findings indicate that either antenatal corticosteroid can be given to women before preterm birth to improve infant and child health. FUNDING: National Health and Medical Research Council (Australia).