Nordic survey showed wide variation in discharge practices for very preterm infants.

AIM: We aimed to describe clinical practices and criteria for discharge of very preterm infants in Nordic neonatal units. METHODS: Medical directors of all 89 level-2 and level-3 units in Denmark, Finland, Iceland, Norway and Sweden were invited by e-mail to complete a web-based multiple-choice survey with the option to make additional free-text comments. RESULTS: We received responses from 83/89 units (93%). In all responding units, discharge readiness was based mainly on clinical assessment with varying criteria. In addition, 36% used formal tests of cardiorespiratory stability and 59% used criteria related to infant weight or growth. For discharge with feeding tube, parental ability to speak the national language or English was mandatory in 45% of units, with large variation among countries. Post-discharge home visits and video-consultations were provided by 59% and 51%, respectively. In 54% of units, parental preparation for discharge were not initiated until the last two weeks of hospital stay. CONCLUSION: Discharge readiness was based mainly on clinical assessment, with criteria varying among units despite similar population characteristics and care structures. This variation indicates a lack of evidence base and may unnecessarily delay discharge; further studies of this matter are needed. Earlier parental preparation and use of interpreters might facilitate earlier discharge.

Lung function deficits and bronchodilator responsiveness at 12 years of age in children born very preterm compared with controls born at term.

INTRODUCTION: Very preterm birth is associated with lung function impairment later in life, but several aspects have not been studied. We aimed to comprehensively assess lung function at school age in very preterm infants and term controls, with special emphasis on bronchopulmonary dysplasia (BPD), sex, and bronchodilator response. METHODS: At 12 years of age, 136 children born very preterm (85 with and 51 without BPD) and 56 children born at term performed spirometry, body plethysmography, impulse oscillometry, measurement of diffusion capacity, and multiple breath washout, before and after bronchodilator inhalation. RESULTS: Airway symptoms and a diagnosis of asthma were more common in children born very preterm. These children had more airflow limitation, seen as lower forced expiratory volume in 1 s (FEV1 ) (p < .001), FEV1 /forced vital capacity (FVC) (p = .011), and mean forced expiratory flow between 25% and 75% of FVC (p < .001), and a higher total and peripheral airway resistance compared with term-born controls. There was no difference in total lung capacity but air trapping and lung clearance index were higher in children born very preterm. Diffusion capacity was lower in children born very preterm, especially in those with a diagnosis of BPD. In most other tests, the differences between preterm-born children with or without BPD were smaller than between children born preterm versus at term. Boys born preterm had more lung function deficits than preterm-born girls. In children born very preterm, airway obstruction was to a large extent reversible. CONCLUSION: At 12 years of age, children born very preterm had lower lung function than children born at term in most aspects and there was only little difference between children with or without BPD. Airway obstruction improved markedly after bronchodilator inhalation.

Patterns of Respiratory Support by Gestational Age in Very Preterm Infants.

INTRODUCTION: A detailed understanding of respiratory support patterns in preterm infants is lacking. The aim was to explore and visualize this practice in Sweden. METHODS: Preterm infants with gestational ages of 22-31 weeks, admitted to neonatal units reporting daily to the Swedish Neonatal Quality Register and discharged alive in November 2015-April 2022, were included in this descriptive cohort study. Proportions receiving mechanical ventilation, noninvasive support, or supplemental oxygen were calculated and graphically displayed for each gestational week and postnatal day (range 0-97) up to hospital discharge or 36 weeks of postmenstrual age. RESULTS: Respiratory support in 148,515 days of care (3,368 infants; 54% males; median [interquartile range] birthweight = 1,215 [900-1,525] g) was evaluated. Trajectories showed distinct nonlinear patterns for each category of respiratory support, but differences in respiratory support over the gestational age range were linear: the proportion of infants on mechanical ventilation decreased by -11.7 to -7.3% (variability in estimates related to the postnatal day chosen for regression analysis) for each week higher gestational age (r = -0.99 to -0.87, p ≤ 0.001). The corresponding proportions of infants with supplemental oxygen decreased by -12.4% to -4.5% for each week higher gestational age (r = -0.98 to -0.94, p < 0.001). At 36 weeks of postmenstrual age, dependencies on mechanical ventilation, noninvasive support, and supplemental oxygen varied from 3%, 84%, and 94% at 22 weeks to 0%, 3%, and 5% at 31 weeks of gestational age, respectively. CONCLUSIONS: Respiratory support patterns in very preterm infants follow nonlinear, gestational age-specific postnatal trajectories in a dose-response-related fashion.

Perinatal inflammation relates to early respiratory morbidity and lung function at 12 years of age in children born very preterm.

AIM: Very preterm birth may be associated with lung function impairment later in life. It is not known if this is caused by prematurity per se or by associated perinatal events, such as maternal-foetal inflammation and severity of early neonatal lung disease. We assessed these factors in a prospective cohort of very preterm infants followed from birth to middle school age. METHODS: In 71 infants with a gestational age of median 27.4 (range 23.9-31.7) weeks, pro-inflammatory and modulatory cytokines were measured in umbilical cord blood and in arterial blood sampled at 6, 24 and 72 h after birth, and cumulated cytokine concentrations were calculated as area under the curve (AUC). At median 12.6 (range 12.3-13.5) years of age, pulmonary function testing was done in 53 children. RESULTS: There was a positive correlation between days on mechanical ventilation and AUC for IL-6 (p = 0.001), IL-8 (p = 0.015) and IL-10 (p = 0.006). Infants with bronchopulmonary dysplasia (BPD; n = 32) had higher AUC for the cytokines IL-6, IL-8 and IL-10 than those without BPD (all p < 0.01). Higher levels of AUC for IL-6 at birth correlated with lower forced expiratory volume in 1 s (p = 0.030) and lower mean expiratory flow rate between 25 and 75% of forced vital capacity (p = 0.034). CONCLUSION: Perinatal inflammation, assessed by circulating cytokines in the first three days of life, was associated with BPD and with airway obstruction at 12 years of age.

Association Between Year of Birth and 1-Year Survival Among Extremely Preterm Infants in Sweden During 2004-2007 and 2014-2016.

Importance: Since 2004-2007, national guidelines and recommendations have been developed for the management of extremely preterm births in Sweden. If and how more uniform management has affected infant survival is unknown. Objective: To compare survival of extremely preterm infants born during 2004-2007 with survival of infants born during 2014-2016. Design, Setting and Participants: All births at 22-26 weeks' gestational age (n = 2205) between April 1, 2004, and March 31, 2007, and between January 1, 2014, and December 31, 2016, in Sweden were studied. Prospective data collection was used during 2004-2007. Data were obtained from the Swedish pregnancy, medical birth, and neonatal quality registries during 2014-2016. Exposures: Delivery at 22-26 weeks' gestational age. Main Outcomes and Measures: The primary outcome was infant survival to the age of 1 year. The secondary outcome was 1-year survival among live-born infants who did not have any major neonatal morbidity (specifically, without intraventricular hemorrhage grade 3-4, cystic periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity stage 3-5, or severe bronchopulmonary dysplasia). Results: During 2004-2007, 1009 births (3.3/1000 of all births) occurred at 22-26 weeks' gestational age compared with 1196 births (3.4/1000 of all births) during 2014-2016 (P = .61). One-year survival among live-born infants at 22-26 weeks' gestational age was significantly lower during 2004-2007 (497 of 705 infants [70%]) than during 2014-2016 (711 of 923 infants [77%]) (difference, -7% [95% CI, -11% to -2.2%], P = .003). One-year survival among live-born infants at 22-26 weeks' gestational age and without any major neonatal morbidity was significantly lower during 2004-2007 (226 of 705 infants [32%]) than during 2014-2016 (355 of 923 infants [38%]) (difference, -6% [95% CI, -11% to -1.7%], P = .008). Conclusions and Relevance: Among live births at 22-26 weeks' gestational age in Sweden, 1-year survival improved between 2004-2007 and 2014-2016.

Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants.

BACKGROUND: Club cell secretory protein (CC16) probably has a role in protecting the lung from inflammation. AIM: To evaluate if low levels of CC16 in gastric fluid at birth, reflecting low levels of CC16 in the lung, would be associated with lung inflammation and respiratory morbidity. METHODS: A study of 64 infants with mean gestational age 26.1 weeks. CC16 was analyzed in gastric fluid at birth. CC16, pro-inflammatory cytokines, and MMP-9 were analyzed in tracheal aspirate within 24 h from birth. RESULTS: CC16 in gastric fluid increased with gestational age (P = 0.033). Lower concentrations of CC16 in gastric fluid at birth were associated with higher concentrations of IL-1ß (P = 0.028), TNF-α (P = 0.034), and MMP-9 (P = 0.015) in tracheal aspirate. Infants who needed mechanical ventilation at 24 and 72 h of age had lower CC16 in gastric fluid than those not ventilated at these ages (P = 0.011 and P = 0.024, respectively). Lower CC16 in gastric fluid was associated with higher FiO2 at 6 h (P = 0.009), higher PaCO2 at 24 h (P = 0.03), more ventilator days (P = 0.012) and more days with supplemental oxygen (P = 0.03). Infants who had either died or were still treated with supplemental oxygen at 36 weeks postmenstrual age had lower CC16 in gastric fluid than infants with none of these outcomes (P = 0.049). CONCLUSION: A low CC16 concentration in gastric fluid at birth was associated with increased inflammation in the trachea within the first 24 h of life and with more need for respiratory support in the neonatal period.

Underlying maternal and pregnancy-related conditions account for a substantial proportion of neonatal morbidity in late preterm infants.

AIM: We studied the impact of maternal and pregnancy-related conditions and the effect of gestational age itself, on the health of infants born late preterm. METHODS: Singletons born in gestational weeks 34 + 0 to 41 + 6 in 1995-2013 in the southern region of Sweden were identified from a perinatal register. We found 14 030 infants born late preterm and 294 814 born at term. A hierarchical system was developed to examine the impact of pregnancy complications. The outcomes studied were as follows: neonatal death, central nervous system (CNS) or respiratory disease, infection, neonatal admission and respiratory support. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained using logistic regression analyses. RESULTS: Late preterm infants were at increased risk for all outcomes compared to term infants, with adjusted ORs from 13.1 (95% CI: 12.7-13.6) for neonatal admission to 2.3 (95% CI: 1.8-2.9) for infections. Late preterm birth after preterm prelabour rupture of membranes was associated with an overall lower risk compared to late preterm births due to other causes. Exposure to antepartum haemorrhage or maternal diabetes increased the risk for CNS and respiratory morbidity. CONCLUSION: Morbidity decreased in late preterm infants with increasing gestational age. Underlying conditions accounted for a substantial part of the morbidity.

Survey shows large differences between the Nordic countries in the use of less invasive surfactant administration.

AIM: Less invasive surfactant administration (LISA), namely surfactant instillation through a thin catheter in the trachea during spontaneous breathing, is increasingly used for premature infants. We surveyed the use of this technique in the Nordic countries in autumn 2015. METHODS: A link to a web-based survey of surfactant administration methods was emailed to the directors of all neonatal units in the Nordic Region, apart from Finland, where only the five university-based departments were invited. RESULTS: Of the 73 units (85%) who responded, 23 (32%) said that they used LISA. The country rates were Iceland 100%, Norway 82%, Finland 60%, Denmark, including Faroe Island and Greenland, 11% and Sweden 9%. LISA was used in 62% of level three units, but only 14% of level two units and most commonly in babies with a gestational age of at least 26 weeks. Premedication was always or sometimes used by 78%. The main reasons for not using LISA were lack of familiarity with the technique (61%), no perceived benefit over other methods (22%) and concerns about patient discomfort (26%). CONCLUSION: Less invasive surfactant administration was used in 32% of Nordic neonatal units, most commonly in level three units. Premedication was used more often than previously reported.

Rapid test for lung maturity, based on spectroscopy of gastric aspirate, predicted respiratory distress syndrome with high sensitivity.

AIM: Respiratory distress syndrome (RDS) is a major cause of mortality and morbidity in premature infants. By the time symptoms appear, it may already be too late to prevent a severe course, with bronchopulmonary dysplasia or mortality. We aimed to develop a rapid test of lung maturity for targeting surfactant supplementation. METHODS: Concentrations of the most surface-active lung phospholipid dipalmitoylphosphatidylcholine and sphingomyelin in gastric aspirates from premature infants were measured by mass spectrometry and expressed as the lecithin/sphingomyelin ratio (L/S). The same aspirates were analysed with mid-infrared spectroscopy. Subsequently, L/S was measured in gastric aspirates and oropharyngeal secretions from another group of premature infants using spectroscopy and the results were compared with RDS development. The 10-minute analysis required 10 µL of aspirate. RESULTS: An L/S algorithm was developed based on 89 aspirates. Subsequently, gastric aspirates were sampled in 136 infants of 24-31 weeks of gestation and 61 (45%) developed RDS. The cut-off value of L/S was 2.2, sensitivity was 92%, and specificity was 73%. In 59 cases, the oropharyngeal secretions had less valid L/S than gastric aspirate results. CONCLUSION: Our rapid test for lung maturity, based on spectroscopy of gastric aspirate, predicted RDS with high sensitivity.

Early surfactant guided by lamellar body counts on gastric aspirate in very preterm infants.

BACKGROUND: We have developed a rapid method, based on lamellar body counts (LBC) on gastric aspirate, for identifying newborns who will develop respiratory distress syndrome with a need for surfactant supplementation. OBJECTIVE: We set out to test whether it was possible to improve the outcome when used in a clinical trial. METHODS: We randomly assigned 380 infants born at 24-29 weeks' gestation and supported with nasal continuous positive airway pressure (nCPAP) to receive surfactant guided either by LBC (intervention group) or increasing need for oxygen (control group). The primary outcome was mechanical ventilation or death within 5 days. Secondary outcomes included need for oxygen expressed by arterial to alveolar oxygen tension ratio (a/APO2) at the age of 6 h and need for oxygen at day 28. RESULTS: The primary outcomes were equal (25%) in the two groups. The intervention group had higher a/APO2 than the control group at 6 h, median 0.64 versus 0.52 (p < 0.01), and the subgroup with gestational age 26-29 weeks needed fewer days of oxygen supplementation than the controls, median 2 vs. 9 days (p = 0.01), and fewer infants needed oxygen at day 28 (p = 0.04). Furthermore, there was a tendency in the intervention group towards a shorter duration of nCPAP. Too little or viscose aspirate in 23% of the cases was a limitation of the method. CONCLUSION: Using LBC test as indicator of lung maturity and early surfactant therapy in very preterm newborns, it is possible to reduce the need for oxygen supplementation.

Clinical experience of urine D-arabinitol/L-arabinitol ratio in the early diagnosis of invasive candidiasis in paediatric high risk populations.

In 2 prospective studies, we previously reported on the early and accurate diagnosis of invasive candidiasis by determining the D-arabinitol/L-arabinitol (DA/LA) ratio in urine in neutropenic children with cancer at the paediatric oncology unit (POU) and in premature infants at the neonatal intensive care unit (NICU) at our hospital. In this retrospective study at the same units, we report how the DA/LA assay was implemented in clinical practice immediately after the prospective study periods. We found that, in the POU, the recommendation of regularly monitoring urine DA/LA ratios in patients at risk and considering antifungal therapy in the case of elevated ratios had been followed. A significant decrease in the incidence of culture positive invasive candidiasis may have been attributed to the introduction of the DA/LA assay. At the NICU, where the DA/LA assay was recommended only as an adjunct to other diagnostic tools, morbidity in invasive candidiasis remained unchanged. While regular monitoring of the urine DA/LA ratio probably facilitates the early detection of invasive candidiasis in paediatric oncology, it remains to be determined if the test can be used in a similar way in neonatal intensive care.

Earlier Apgar score increase in severely depressed term infants cared for in Swedish level III units with 40% oxygen versus 100% oxygen resuscitation strategies: a population-based register study.

OBJECTIVES: The aim of this study was to evaluate whether a resuscitation strategy based on administration of 40% oxygen influences mortality rates and rates of improvement in 5-minute Apgar scores, compared with a strategy based on 100% oxygen administration. METHODS: A population-based study evaluated data from 4 Swedish perinatal level III centers during the period of 1998 to 2003. During this period, the centers used either of 2 resuscitation strategies (initial oxygen administration of 40% or 100%). Live-born, singleton, term infants with 1-minute Apgar scores of <4, with a birth weight appropriate for gestational age, and without major malformations were included in the study (n = 1223). RESULTS: Infants born in hospitals using a 40% oxygen strategy had a more rapid Apgar score increase than did infants born in hospitals using a 100% oxygen strategy; however, no difference remained at 10 minutes. The mean Apgar score increased from 2.01 at 1 minute to 6.74 at 5 minutes in the 2 hospitals initiating resuscitation with 40% oxygen, compared with 2.01 to 6.38 in the 2 hospitals using 100% oxygen, with a mean difference in Apgar score increases of 0.36. At 5 minutes, 44.3% of infants born in the hospitals using 100% oxygen had an Apgar score of <7, compared with 34.0% of infants at the hospitals using 40% oxygen. At 10 minutes, the mean Apgar scores were 8.16 at the hospitals using 40% oxygen and 8.07 at the hospitals using 100% oxygen. There were no significant differences in rates of neonatal death, hypoxic ischemic encephalopathy, or seizures in relation to the 2 oxygen strategies. CONCLUSION: Severely depressed term infants born in hospitals initiating resuscitation with 40% oxygen had earlier Apgar score recovery than did infants born in hospitals using a 100% oxygen strategy.

Massive feto-maternal hemorrhage: diagnosis by cardiotocography, Doppler ultrasonography and ST waveform analysis of fetal electrocardiography.

A 34-year-old healthy gravida 2 para 1 presented after an uncomplicated pregnancy at term with a 2-day history of diminished fetal movements. Fetal anemia was suspected by fetal heart rate monitoring and Doppler estimation of the fetal peak blood flow velocity of the middle cerebral artery. We were also fortunate to register pathological ST waveform changes of the fetal ECG indicating fetal hypoxia. The diagnosis of a massive feto-maternal hemorrhage was confirmed by an extremely high fraction of erythrocytes containing fetal hemoglobin in maternal blood and, after delivery, by placental histology.

Incomplete protection by prophylactic surfactant against the adverse effects of large lung inflations at birth in immature lambs.

OBJECTIVE: To investigate whether preceding surfactant instillation prevents the harmful effect of large lung inflations at birth in immature lambs, and, if not, to find out for how long the immature lung remains sensitive to large inflations. DESIGN: In an exploratory study, 12 preterm lambs given surfactant at birth were randomized to receive five large lung inflations at four different times: at birth just before or immediately after surfactant treatment; at 10 min; or at 60 min of age. In a confirmatory study, 10 pairs of preterm lamb twins were all given surfactant before the first breath. One lamb in each pair was randomised to receive large lung inflations immediately after surfactant while the other twin underwent similar inflations at 10-15 min of age. SETTING: Animal laboratory. EXPERIMENTAL ANIMALS: Anaesthetized lambs delivered by cesarean section at a gestational age of 127 days. INTERVENTIONS: Surfactant supplementation at birth. Five sustained lung inflations of 16 ml/kg at different times in relation to surfactant instillation. Pressure-limited mechanical ventilation for 4 h. MEASUREMENTS AND RESULTS: The response to surfactant was assessed by ventilator settings, lung mechanics and lung histology. Preceding surfactant supplementation did not prevent the adverse effect of large lung inflations at birth on ventilatory efficiency and lung mechanics, but seemed to protect against severe lung injury. No adverse effect was seen from large lung inflations given at 10 min of age or later. CONCLUSION: Prophylactic surfactant supplementation does not fully protect against the harmful effect of large lung inflations during a short sensitive period immediately after birth.