Fetal haemoglobin and oxygen requirement in preterm infants: an observational study.

OBJECTIVE: To investigate the relationship between the fraction of fetal haemoglobin (HbF(%)) and oxygen requirement as determined by the fraction of inspired oxygen (FiO2) and alveolar-arterial gradient (A-a gradient). Increased alveolar exposure to oxygen may explain the association between decreased HbF(%) and the development of bronchopulmonary dysplasia (BPD). DESIGN: Longitudinal, retrospective, observational study. SETTING: Tertiary-level neonatal intensive care unit, referral centre for southern Sweden. PATIENTS: Four hundred forty very preterm infants born before gestational week 30, 2009-2015. INTERVENTION: Regular clinical practice. MAIN OUTCOME MEASURES: The FiO2 and A-a gradient were determined at the time-point of 10 015 arterial blood gas analyses obtained during postnatal days 1-7. The relationship between HbF(%) and FiO2 and A-a gradient and the modifying influence of other factors affecting haemoglobin oxygen affinity were evaluated. RESULTS: We found a significant relationship between a low fraction of HbF and an increase in FiO2 and A-a gradient, respectively. These relationships remained significant after adjusting for pH, pCO2, postnatal age, gestational age and sex. CONCLUSION: These high-resolution data show that decreased HbF(%) during the first postnatal week is associated with increased FiO2 and A-a gradient in very preterm infants. Increased alveolar exposure to oxygen and resulting oxidative stress may, at least partly, explain the previously reported associations between decreased HbF, blood transfusions and the development of BPD in preterm infants.

Evaluation of recombinant human IGF-1/IGFBP-3 on intraventricular hemorrhage prevention and survival in the preterm rabbit pup model.

Insulin-like growth factor-1 (IGF-1) is essential for normal brain development and regulates processes of vascular maturation. The pathogenesis of intraventricular hemorrhage (IVH) relates to the fragility of the immature capillaries in the germinal matrix, and its inability to resist fluctuations in cerebral blood flow. In this work, using different experimental setups, we aimed to (i) establish an optimal time-point for glycerol-induction of IVH in relation to time-point of recombinant human (rh) IGF-1/rhIGFBP-3 administration, and (ii) to evaluate the effects of a physiologic replacement dose of rhIGF-1/rhIGFBP-3 on prevention of IVH and survival in the preterm rabbit pup. The presence of IVH was evaluated using high-frequency ultrasound and post-mortem examinations. In the first part of the study, the highest incidence of IVH (> 60%), occurred when glycerol was administered at the earliest timepoint, e.g., 6 h after birth. At later time-points (18 and 24 h) the incidence decreased substantially. In the second part of the study, the incidence of IVH and mortality rate following rhIGF-1/rhIGFBP-3 administration was not statistically different compared to vehicle treated animals. To evaluate the importance of maintaining intrauterine serum levels of IGF-1 following preterm birth, as reported in human interventional studies, additional studies are needed to further characterize and establish the potential of rhIGF-1/rhIGFBP-3 in reducing the prevalence of IVH and improving survival in the preterm rabbit pup.

Perioperative brain injury marker concentrations in neonatal open-heart surgery: a prospective observational study.

Neonates with critical congenital heart defects undergoing open-heart surgery on cardiopulmonary bypass circulation are at risk for white matter brain injury. This article reports on pre- and postoperative plasma concentrations of brain injury markers glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and Tau, and their respective associations with white matter lesions detected on postoperatively performed brain MRI. Forty term newborns with isolated critical congenital heart defects were included in a prospective observational study. Brain injury marker plasma concentrations were determined prior to surgery and at postoperative days 1, 2 and 3. Brain magnetic resonance imaging was performed pre- and postoperatively. Concentrations of brain injury markers were analysed using ultrasensitive single molecule array technology. Absolute pre- and postoperative plasma biomarker concentrations, and postoperative concentrations adjusted for preoperative concentrations were used for subsequent analysis. Plasma concentrations of GFAP, NfL and Tau displayed a well-defined temporal trajectory after neonatal cardiopulmonary bypass circulation. GFAP and Tau reached peak concentrations at postoperative day 2 (median concentrations 170.5 and 67.2 pg/ml, respectively), whereas NfL continued to increase throughout the study period (median concentration at postoperative day 3 191.5 pg/ml). Adjusted Tau at postoperative day 2 was significantly higher in infants presenting with white matter lesions on postoperative MRI compared to infants without white matter injury.

One-year survival and outcomes of infants born at 22 and 23 weeks of gestation in Sweden 2004-2007, 2014-2016 and 2017-2019.

OBJECTIVE: To explore associations between perinatal activity and survival in infants born at 22 and 23 weeks of gestation in Sweden. DESIGN/SETTING: Data on all births at 22 and 23 weeks' gestational age (GA) were prospectively collected in 2004-2007 (T1) or obtained from national registers in 2014-2016 (T2) and 2017-2019 (T3). Infants were assigned perinatal activity scores based on 3 key obstetric and 4 neonatal interventions. MAIN OUTCOME: One-year survival and survival without major neonatal morbidities (MNM): intraventricular haemorrhage grade 3-4, cystic periventricular leucomalacia, surgical necrotising enterocolitis, retinopathy of prematurity stage 3-5 or severe bronchopulmonary dysplasia. The association of GA-specific perinatal activity score and 1-year survival was also determined. RESULTS: 977 infants (567 live births and 410 stillbirths) were included: 323 born in T1, 347 in T2 and 307 in T3. Among live-born infants, survival at 22 weeks was 5/49 (10%) in T1 and rose significantly to 29/74 (39%) in T2 and 31/80 (39%) in T3. Survival was not significantly different between epochs at 23 weeks (53%, 61% and 67%). Among survivors, the proportions without MNM in T1, T2 and T3 were 20%, 17% and 19% for 22 weeks and 17%, 25% and 25% for 23 weeks' infants (p>0.05 for all comparisons). Each 5-point increment in GA-specific perinatal activity score increased the odds for survival in first 12 hours of life (adjusted OR (aOR) 1.4; 95% CI 1.3 to 1.6) in addition to 1-year survival (aOR 1.2; 95% CI 1.1 to 1.3), and among live-born infants it was associated with increased survival without MNM (aOR 1.3; 95% CI 1.1 to 1.4). CONCLUSION: Increased perinatal activity was associated with reduced mortality and increased chances of survival without MNM in infants born at 22 and 23 weeks of GA.

Neonatal outcomes following early fetal growth restriction: a subgroup analysis of the EVERREST study.

OBJECTIVE: To quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR). DESIGN: The EVERREST (Do e s v ascular endothelial growth factor gene therapy saf e ly imp r ove outcome in seve r e e arly-onset fetal growth re st riction?) prospective multicentre study of women diagnosed with EP-FGR (singleton, estimated fetal weight (EFW) <3rd percentile, <600 g, 20+0-26+6 weeks of gestation). The UK subgroup of EP-FGR infants (<36 weeks) were sex-matched and gestation-matched to appropriate for age (AGA) infants born in University College London Hospital (1:2 design, EFW 25th-75th percentile). SETTING: Four tertiary perinatal units (UK, Germany, Spain, Sweden). MAIN OUTCOMES: Antenatal and postnatal mortality, bronchopulmonary dysplasia (BPD), sepsis, surgically treated necrotising enterocolitis (NEC), treated retinopathy of prematurity (ROP). RESULTS: Of 135 mothers recruited with EP-FGR, 42 had a stillbirth or termination of pregnancy (31%) and 93 had live births (69%). Postnatal genetic abnormalities were identified in 7/93 (8%) live births. Mean gestational age at birth was 31.4 weeks (SD 4.6). 54 UK-born preterm EP-FGR infants (<36 weeks) were matched to AGA controls. EP-FGR was associated with increased BPD (43% vs 26%, OR 3.6, 95% CI 1.4 to 9.4, p=0.01), surgical NEC (6% vs 0%, p=0.036) and ROP treatment (11% vs 0%, p=0.001). Mortality was probably higher among FGR infants (9% vs 2%, OR 5.0, 95% CI 1.0 to 25.8, p=0.054). FGR infants more frequently received invasive ventilation (65% vs 50%, OR 2.6, 95% CI 1.1 to 6.1, p=0.03), took longer to achieve full feeds and had longer neonatal stays (median difference 6.1 days, 95% CI 3.8 to 8.9 and 19 days, 95% CI 9 to 30 days, respectively, p<0.0001). CONCLUSIONS: Mortality following diagnosis of EP-FGR is high. Survivors experience increased neonatal morbidity compared with AGA preterm infants. TRIAL REGISTRATION NUMBER: NCT02097667.

Postnatal serum IGF-1 levels associate with brain volumes at term in extremely preterm infants.

BACKGROUND: Growth factors important for normal brain development are low in preterm infants. This study investigated the link between growth factors and preterm brain volumes at term. MATERIAL/METHODS: Infants born <28 weeks gestational age (GA) were included. Endogenous levels of insulin-like growth factor (IGF)-1, brain-derived growth factor, vascular endothelial growth factor, and platelet-derived growth factor (expressed as area under the curve [AUC] for serum samples from postnatal days 1, 7, 14, and 28) were utilized in a multivariable linear regression model. Brain volumes were determined by magnetic resonance imaging (MRI) at term equivalent age. RESULTS: In total, 49 infants (median [range] GA 25.4 [22.9-27.9] weeks) were included following MRI segmentation quality assessment and AUC calculation. IGF-1 levels were independently positively associated with the total brain (p < 0.001, ß = 0.90), white matter (p = 0.007, ß = 0.33), cortical gray matter (p = 0.002, ß = 0.43), deep gray matter (p = 0.008, ß = 0.05), and cerebellar (p = 0.006, ß = 0.08) volume adjusted for GA at birth and postmenstrual age at MRI. No associations were seen for other growth factors. CONCLUSIONS: Endogenous exposure to IGF-1 during the first 4 weeks of life was associated with total and regional brain volumes at term. Optimizing levels of IGF-1 might improve brain growth in extremely preterm infants. IMPACT: High serum levels of insulin-like growth factor (IGF)-1 during the first month of life were independently associated with increased total brain volume, white matter, gray matter, and cerebellar volume at term equivalent age in extremely preterm infants. IGF-1 is a critical regulator of neurodevelopment and postnatal levels are low in preterm infants. The effects of IGF-1 levels on brain development in extremely preterm infants are not fully understood. Optimizing levels of IGF-1 may benefit early brain growth in extremely preterm infants. The effects of systemically administered IGF-1/IGFBP3 in extremely preterm infants are now being investigated in a randomized controlled trial (Clinicaltrials.gov: NCT03253263).

Fetal growth restriction followed by very preterm birth is associated with smaller kidneys but preserved kidney function in adolescence.

BACKGROUND: Preterm birth and fetal growth restriction (FGR) are associated with structural and functional kidney changes, increasing long-term risk for chronic kidney disease and hypertension. However, recent studies in preterm children are conflicting, indicating structural changes but normal kidney function. This study therefore assessed kidney structure and function in a cohort of adolescents born very preterm with and without verified FGR. METHODS: Adolescents born very preterm with FGR and two groups with appropriate birthweight (AGA) were included; one matched for gestational week at birth and one born at term. Cortical and medullary kidney volumes and T1 and T2* mapping values were assessed by magnetic resonance imaging. Biochemical markers of kidney function and renin-angiotensin-aldosterone system (RAAS) activation were analyzed. RESULTS: Sixty-four adolescents were included (13-16 years; 48% girls). Very preterm birth with FGR showed smaller total (66 vs. 75 ml/m2; p = 0.01) and medullary volume (19 vs. 24 ml/m2; p < 0.0001) compared to term AGA. Corticomedullary volume ratio decreased from preterm FGR (2.4) to preterm AGA (2.2) to term AGA (1.9; p = 0.004). There were no differences in T1 or T2* values (all p ≥ 0.34) or in biochemical markers (all p ≥ 0.12) between groups. CONCLUSIONS: FGR with abnormal fetal blood flow followed by very preterm birth is associated with smaller total kidney and medullary kidney volumes, but not with markers of kidney dysfunction or RAAS activation in adolescence. Decreased total kidney and medullary volumes may still precede a long-term decrease in kidney function, and potentially be used as a prognostic marker. A higher resolution version of the Graphical abstract is available as Supplementary information.

Cell-Free Hemoglobin Concentration in Blood Prime Solution Is a Major Determinant of Cell-Free Hemoglobin Exposure during Cardiopulmonary Bypass Circulation in the Newborn.

Exposure to circulating cell-free hemoglobin is a ubiquitous feature of open-heart surgery on cardiopulmonary bypass circulation. This study aims to determine the origins and dynamics of circulating cell-free hemoglobin and its major scavenger proteins haptoglobin and hemopexin during neonatal cardiopulmonary bypass. Forty neonates with an isolated critical congenital heart defect were included in a single-center prospective observational study. Blood samples were obtained preoperatively, hourly during bypass circulation, after bypass separation, at admission to the pediatric intensive care unit, and at postoperative days 1-3. Concentrations of cell-free hemoglobin, haptoglobin and hemopexin were determined using ELISA. Neonates were exposed to significantly elevated plasma concentrations of cell-free hemoglobin and a concomitant depletion of scavenger protein supplies during open-heart surgery. The main predictor of cell-free hemoglobin exposure was the concentration of cell-free hemoglobin in blood prime solution. Concentrations of haptoglobin and hemopexin in prime solution were important determinants for intra- and postoperative circulating scavenger protein resources.

Preterm infant circulating sex steroid levels are not altered by transfusion with adult male plasma: a retrospective multicentre cohort study.

OBJECTIVE: To determine if plasma transfusions with male donor plasma to very preterm infants affect circulatory levels of sex steroids. DESIGN AND PATIENTS: Retrospective multicentre cohort study in 19 infants born at gestational age <29 weeks requiring plasma transfusion during their first week of life. SETTING: Three neonatal intensive care units in Sweden. MAIN OUTCOME MEASURES: Concentrations of sex steroids and sex hormone-binding globulin (SHBG) in donor plasma and infant plasma measured before and after a plasma transfusion and at 6, 12, 24 and 72 hours. RESULTS: The concentrations of progesterone, dehydroepiandrosterone and androstenedione were significantly lower in donor plasma than in infant plasma before the transfusion (median (Q1-Q3) 37.0 (37.0-37.0), 1918 (1325-2408) and 424 (303-534) vs 901 (599-1774), 4119 (2801-14 645) and 842 (443-1684) pg/mL), while oestrone and oestradiol were higher in donor plasma (17.4 (10.4-20.1) and 16.0 (11.7-17.2) vs 3.1 (1.1-10.2) and 0.25 (0.25-0.25) pg/mL). Median testosterone and dihydrotestosterone (DHT) levels were 116-fold and 21-fold higher in donor plasma than pre-transfusion levels in female infants, whereas the corresponding difference was not present in male infants. Plasma sex steroid levels were unchanged after completed transfusion compared with pre-transfusion levels, irrespective of the gender of the receiving infant. The SHBG concentration was significantly higher in donor than in recipient plasma (22.8 (17.1-33.5) vs 10.2 (9.1-12.3) nmol/L) before transfusion but did not change in the infants after the transfusion. CONCLUSIONS: A single transfusion of adult male plasma to preterm infants had no impact on circulating sex steroid levels.

Low fraction of fetal haemoglobin is associated with retinopathy of prematurity in the very preterm infant.

BACKGROUND: Blood loss and adult blood transfusions are common during the neonatal period in preterm infants. The objective of the study was to clarify if degree of loss of fetal haemoglobin (HbF) was associated with later retinopathy of prematurity (ROP). METHODS: Retrospective observational cohort study. In total, 452 infants born <30 gestational weeks at a tertiary level neonatal intensive care unit in Sweden in 2009-2015 were included, 385 of whom had final ROP outcome. Mean fractions of HbF (%) during the first postnatal week were calculated from 11 861 arterial blood gas analyses. The relationship between fractions of HbF (%) and ROP was evaluated. RESULTS: The mean (SD) gestational age (GA) at birth was 26.4 (1.8) weeks. In total, 104 (27 %) infants developed ROP. Higher fraction of HbF (%) was associated with a lower prevalence of ROP, OR by a 10% increase 0.83 (95% CI: 0.71 to 0.97; p=0.019), following adjustment for GA at birth, small for GA and sex. Infants with HbF (%) in the lowest quartile had OR of 22.0 (95% CI: 8.1 to 59.2; p<0.001) for ROP development compared with those in the highest quartile. The predictive ability (area under the curve) of HbF (%) in the full model during the first week was 0.849 for ROP. CONCLUSIONS: Early low fraction of HbF is independently associated with abnormal retinal neurovascular development in the very preterm infant. The potential benefit of minimising blood loss on development of ROP will be investigated in a multicenter randomised trial (NCT04239690).

Systematic review of the healthcare cost of bronchopulmonary dysplasia.

OBJECTIVES: To determine the costs directly or indirectly related to bronchopulmonary dysplasia (BPD) in preterm infants. The secondary objective was to stratify the costs based on gestational age and/or birth weight. DESIGN: Systematic literature review. SETTING: PubMed and Scopus were searched on 3 February 2020. Studies were selected based on eligibility criteria by two independent reviewers. Included studies were further searched to identify eligible references and citations.Two independent reviewers extracted data with a prespecified data extraction sheet, including items from a published checklist for quality assessment. The costs in the included studies are reported descriptively. PRIMARY OUTCOME MEASURE: Costs of BPD. RESULTS: The 13 included studies reported the total costs or marginal costs of BPD. Most studies reported costs during birth hospitalisation (cost range: Int$21 392-Int$1 094 509 per child, equivalent to €19 103-€977 397, in 2019) and/or during the first year of life. One study reported costs during the first 2 years; two other studies reported costs later, during the preschool period and one study included a long-term follow-up. The highest mean costs were associated with infants born at extremely low gestational ages. The quality assessment indicated a low risk of bias in the reported findings of included studies. CONCLUSIONS: This study was the first systematic review of costs associated with BPD. We confirmed previous reports of high costs and described the long-term follow-up necessary for preterm infants with BPD, particularly infants of very low gestational age. Moreover, we identified a need for studies that estimate costs outside hospitals and after the first year of life. PROSPERO REGISTRATION NUMBER: CRD42020173234.

Decreased Platelet Counts and Serum Levels of VEGF-A, PDGF-BB, and BDNF in Extremely Preterm Infants Developing Severe ROP.

INTRODUCTION: Thrombocytopenia has been identified as an independent risk factor for retinopathy of prematurity (ROP), although underlying mechanisms are unknown. In this study, the association of platelet count and serum platelet-derived factors with ROP was investigated. METHODS: Data for 78 infants born at gestational age (GA) <28 weeks were included. Infants were classified as having no/mild ROP or severe ROP. Serum levels of vascular endothelial growth factor A, platelet-derived growth factor BB, and brain-derived neurotrophic factor were measured in serum samples collected from birth until postmenstrual age (PMA) 40 weeks. Platelet counts were obtained from samples taken for clinical indication. RESULTS: Postnatal platelet counts and serum concentrations of the 3 growth factors followed the same postnatal pattern, with lower levels in infants developing severe ROP at PMA 32 and 36 weeks (p < 0.05-0.001). With adjustment for GA, low platelet counts and low serum concentrations of all 3 factors at PMA 32 weeks were significantly associated with severe ROP. Serum concentrations of all 3 factors also strongly correlated with platelet count (p < 0.001). CONCLUSION: In this article, we show that ROP, platelet counts, and specific pro-angiogenic factors correlate. These data suggest that platelet-released factors might be involved in the regulation of retinal and systemic angiogenesis after extremely preterm birth. Further investigations are needed.

Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial.

Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.

Fetal haemoglobin and bronchopulmonary dysplasia in neonates: an observational study.

OBJECTIVE: Early decrease in fetal haemoglobin (HbF) is an indicator of loss of endogenous blood components that might have predictive value for development of bronchopulmonary dysplasia (BPD). The link between HbF and BPD has not been evaluated. DESIGN: Retrospective observational study. SETTING: Tertiary level neonatal intensive care unit, referral centre for Southern Sweden. PATIENTS: 452 very preterm infants (<30 gestational weeks) born 2009-2015. INTERVENTIONS: Regular clinical practice. MAIN OUTCOME MEASURES: Mean HbF, haemoglobin (Hb) and partial oxygen pressure (PaO2) levels calculated from 11 861 arterial blood gas analyses postnatal week 1. Relationship between HbF (%) and BPD (requirement of supplemental oxygen at 36 weeks' postmenstrual age) and the modifying influence of PaO2 (kPa) and total Hb (g/L) was evaluated. RESULTS: The mean gestational age (GA) at birth was 26.4 weeks, and 213 (56%) infants developed BPD. A 10% increase in HbF was associated with a decreased prevalence of BPD, OR 0.64 (95% CI 0.49 to 0.83; p<0.001). This association remained when adjusting for mean PaO2 and Hb. Infants with an HbF in the lowest quartile had an OR of 27.1 (95% CI 11.6 to 63.4; p<0.001) for development of BPD as compared with those in the highest quartile. The area under the curve for HbF levels and development of BPD in the full statistical model was 0.871. CONCLUSIONS: Early rapid postnatal decline in HbF levels was associated with development of BPD in very preterm infants. The association between HbF and BPD was not mediated by increased oxygen exposure. The potential benefit of minimising loss of endogenous blood components on BPD outcome will be investigated in a multicentre randomised trial.

Hyponatraemia despite isotonic maintenance fluid therapy: a time series intervention study.

OBJECTIVE: To examine the prevalence of dysnatraemias among children admitted for paediatric surgery before and after a change from hypotonic to isotonic intravenous maintenance fluid therapy. DESIGN: Retrospective consecutive time series intervention study. SETTING: Paediatric surgery ward at the Children's Hospital in Lund, during a 7-year period, 2010-2017. PATIENTS: All children with a blood sodium concentration measurement during the study period were included. Hypotonic maintenance fluid (40 mmol/L NaCl and 20 mmol/L KCl) was used during the first 3 years of the study (646 patients), and isotonic solution (140 mmol/L NaCl and 20 mmol/L KCl) was used during the following period (807 patients). MAIN OUTCOME MEASURES: Primary outcomes were sodium concentration and occurrence of hyponatraemia (<135 mmol/L) or hypernatraemia (>145 mmol/L). RESULTS: Overall, the change from hypotonic to isotonic intravenous maintenance fluid therapy was associated with a decreased prevalence of hyponatraemia from 29% to 22% (adjusted OR 0.65 (0.51-0.82)) without a significantly increased odds for hypernatraemia (from 3.4% to 4.3%, adjusted OR 1.2 (0.71-2.1)). Hyponatraemia <130 mmol/L decreased from 6.2% to 2.6%, and hyponatraemia <125 mmol/L decreased from 2.0% to 0.5%. CONCLUSIONS: Routine use of intravenous isotonic maintenance fluids was associated with lower prevalence of hyponatraemia, although hyponatraemia still occurred in over 20% of patients. We propose that the composition and the volume of administered fluid need to be addressed.

Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.

BACKGROUND: Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of mortality and long-term neurological sequelae, affecting thousands of children worldwide. Current therapies to treat HIE are limited to cooling. Stem cell-based therapies offer a potential therapeutic approach to repair or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal trials. OBJECTIVES: To determine the efficacy and safety of stem cell-based interventions for the treatment of hypoxic-ischaemic encephalopathy (HIE) in newborn infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 5), MEDLINE via PubMed (1966 to 8 June 2020), Embase (1980 to 8 June 2020), and CINAHL (1982 to 8 June 2020). 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 controlled trials, quasi-randomised controlled trials and cluster trials comparing 1) stem cell-based interventions (any type) compared to control (placebo or no treatment); 2) use of mesenchymal stem/stromal cells (MSCs) of type (e.g. number of doses or passages) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus MSCs of other type or source; 3) use of stem cell-based interventions other than MSCs of type (e.g. mononuclear cells, oligodendrocyte progenitor cells, neural stem cells, hematopoietic stem cells, and inducible pluripotent stem cells) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus stem cell-based interventions other than MSCs of other type or source; or 4) MSCs versus stem cell-based interventions other than MSCs. DATA COLLECTION AND ANALYSIS: For each of the included trials, two authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs or other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, death or major neurodevelopmental disability assessed at 18 to 24 months of age. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS: Our search strategy yielded 616 references. Two review authors independently assessed all references for inclusion. We did not find any completed studies for inclusion. Fifteen RCTs are currently registered and ongoing. We describe the three studies we excluded. AUTHORS' CONCLUSIONS: There is currently no evidence from randomised trials that assesses the benefit or harms of stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.

Elevated levels of IL-6 and IGFBP-1 predict low serum IGF-1 levels during continuous infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants.

OBJECTIVE: Steady state insulin-like growth factor-1 (IGF-1) levels vary significantly during continuous intravenous infusion of recombinant human insulin-like growth factor-1/recombinant human insulin-like growth factor binding protein-3 (rhIGF-1/rhIGFBP-3) in the first weeks of life in extremely preterm infants. We evaluated interleukin-6 (IL-6) and insulin-like growth factor binding protein-1 (IGFBP-1) levels as predictors of low IGF-1 levels. METHODS: Nineteen extremely preterm infants were enrolled in a trial, 9 received rhIGF-1/rhIGFBP-3 and 10 received standard neonatal care. Blood samples were analyzed daily for IGF-1, IL-6 and IGFBP-1 during intervention with rhIGF-1/rhIGFBP-3. RESULTS: Thirty seven percent of IGF-1 values during active treatment were <20 µg/L. Among treated infants, higher levels of IL-6, one and two days before sampled IGF-1, were associated with IGF-1 < 20 µg/L, gestational age adjusted OR 1.30 (95% CI 1.03-1.63), p = .026, and 1.57 (95% CI 1.26-1.97), p < .001 respectively. Higher levels of IGFBP-1 one day before sampled IGF-1 was also associated with IGF-1 < 20 µg/L, gestational age adjusted OR 1.74 (95% CI 1.19-2.53), p = .004. CONCLUSION: In preterm infants receiving continuous infusion of rhIGF-1/rhIGFBP-3, higher levels of IL-6 and IGFBP-1 preceded lower levels of circulating IGF-1. These findings demonstrate a need to further evaluate if inflammation and/or infection suppress serum IGF-1 levels. The trial is registered at ClinicalTrials.gov (NCT01096784).

Neonatal clinical blood sampling led to major blood loss and was associated with bronchopulmonary dysplasia.

AIM: Studies indicate that reduced foetal haemoglobin levels are related to increased neonatal morbidity rates. This study investigated the relationships between sampling-related blood loss and adult blood transfusions administered during postnatal days 1-14 and the development of severe neonatal morbidities in extremely preterm infants born before 28 weeks of gestation. METHODS: The medical files of 149 extremely preterm infants born at two university hospitals in Sweden from 2013 to 2018 were investigated. RESULTS: Blood sampling resulted in a 58% depletion of the endogenous blood volume postnatal days 1-14 (median 40.4 mL/kg, interquartile range 23.9-53.3 mL/kg) and correlated with the adult erythrocyte transfusion volume (rS  = 0.870, P < .001). Sampling-related blood loss on postnatal days 1-7, adjusted for gestational age at birth and birth weight standard deviation score, was associated with the development of bronchopulmonary dysplasia (BPD) (odds ratio by a 10-unit increase 2.4, 95% confidence interval 1.1-5.4) (P = .03). No associations were found between blood sampling and intraventricular haemorrhage or necrotising enterocolitis in the full statistical model. The largest proportion of sampling-related blood was used for blood gas analyses (48.7%). CONCLUSION: Diagnostic blood sampling led to major endogenous blood loss replaced with adult blood components and was associated with the development of BPD.

Intraventricular Hemorrhage and White Matter Injury in Preclinical and Clinical Studies.

Germinal matrix-intraventricular hemorrhage (IVH) occurs in nearly half of infants born at less than 26 weeks' gestation. Up to 50% of survivors with IVH develop cerebral palsy, cognitive deficits, behavioral disorders, posthemorrhagic ventricular dilatation, or a combination of these sequelae. After the initial bleeding and the primary brain injury, inflammation and secondary brain injury might lead to periventricular leukomalacia or diffuse white matter injury. Potential factors that are involved include microglia and astrocyte activation, degradation of blood components with release of "toxic" products, infiltration of the brain by systemic immune cells, death of neuronal and glial cells, and arrest of preoligodendrocyte maturation. In addition, impairment of the blood-brain barrier may play a major role in the pathophysiology. A wide range of animal models has been used to explore causes and mechanisms leading to IVH-induced brain injury. Preclinical studies have identified potential targets for enhancing brain repair. However, little has been elucidated about the effectiveness of potential interventions in clinical studies. A systematic review of available preclinical and clinical studies might help identify research gaps and which types of interventions may be prioritized. Future trials should report clinically robust and long-term outcomes after IVH.

[Extremely preterm birth in Sweden - clear progress but remaining challenges]. / Extremt förtidig födelse ­ svåra utmaningar trots stora framsteg - Överlevnaden till 1 års ålder är hög, men allvarlig neonatal sjuklighet är en utmaning.

The recently documented high survival of extremely preterm infants in Sweden is related to a high degree of centralization of pre- and postnatal care and to recently issued national consensus guidelines providing recommendations for perinatal care at 22-24 gestational weeks. The prevalence of major neonatal morbidity remains high and exceeded 60 % in a recent study of extremely preterm infants born at < 27 gestational weeks delivered in Sweden in 2014-2016 and surviving to 1 year of age. Damage to immature organ systems inflicted during the neonatal period causes varying degrees of functional impairment with lasting effects in the growing child. There is an urgent need for evidence-based novel interventions aiming to prevent neonatal morbidity with a subsequent improvement of long-term outcome.