Probiotic supplementation and risk of necrotizing enterocolitis and mortality among extremely preterm infants-the Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial: study protocol for a multicenter, double-blinded, placebo-controlled, and registry-based randomized controlled trial.

BACKGROUND: Extremely preterm infants, defined as those born before 28 weeks' gestational age, are a very vulnerable patient group at high risk for adverse outcomes, such as necrotizing enterocolitis and death. Necrotizing enterocolitis is an inflammatory gastrointestinal disease with high incidence in this cohort and has severe implications on morbidity and mortality. Previous randomized controlled trials have shown reduced incidence of necrotizing enterocolitis among older preterm infants following probiotic supplementation. However, these trials were underpowered for extremely preterm infants, rendering evidence for probiotic supplementation in this population insufficient to date. METHODS: The Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial is a multicenter, double-blinded, placebo-controlled and registry-based randomized controlled trial conducted among extremely preterm infants (n = 1620) born at six tertiary neonatal units in Sweden and four units in Denmark. Enrolled infants will be allocated to receive either probiotic supplementation with ProPrems® (Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus) diluted in 3 mL breastmilk or placebo (0.5 g maltodextrin powder) diluted in 3 mL breastmilk per day until gestational week 34. The primary composite outcome is incidence of necrotizing enterocolitis and/or mortality. Secondary outcomes include incidence of late-onset sepsis, length of hospitalization, use of antibiotics, feeding tolerance, growth, and body composition at age of full-term and 3 months corrected age after hospital discharge. DISCUSSION: Current recommendations for probiotic supplementation in Sweden and Denmark do not include extremely preterm infants due to lack of evidence in this population. However, this young subgroup is notably the most at risk for experiencing adverse outcomes. This trial aims to investigate the effects of probiotic supplementation on necrotizing enterocolitis, death, and other relevant outcomes to provide sufficiently powered, high-quality evidence to inform probiotic supplementation guidelines in this population. The results could have implications for clinical practice both in Sweden and Denmark and worldwide. TRIAL REGISTRATION: ( Clinicaltrials.gov ): NCT05604846.

Blood pressure trends following birth in infants born under 25 weeks' gestational age: a retrospective cohort study.

OBJECTIVE: The aim of our study was to describe postnatal blood pressure (BP) trends and evaluate relevant dynamics and outcomes for a subgroup of extremely preterm (EPT) infants. DESIGN: Retrospective observational cohort study. SETTING: Patients admitted to Karolinska University Hospital Stockholm. PATIENTS: EPT infants born between 22+0 and 24+6 weeks' gestational age (GA) undergoing invasive, continuous BP monitoring through an umbilical arterial catheter. MAIN OUTCOME MEASURES: Physiological BP trends, the influence of cardiovascular active interventions and fluid boluses on BP, and relevant adverse outcomes, including intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC) and death, were mapped over the first week of life. RESULTS: We included 125 infants between January 2009 and November 2021. Mean BP values were 31 mm Hg, 32 mm Hg and 35 mm Hg, at 3 hours, 24 hours and 48 hours, respectively. A pronounced BP dip and nadir were observed around 20 hours, with a mean BP value of 32 mm Hg. 84% received fluid boluses within the first week of life; however, we could not observe any noteworthy change in BP following administration. Only 8% of patients received cardiovascular active drugs, which were too few to infer drug-specific effects. Overall, 48% developed IVH, 15% developed NEC and 25% died. CONCLUSIONS: Approximating clinically acceptable mean BP values using GA gives underestimations in these infants. The postnatal BP dip should be regarded as a physiological phenomenon and not automatic grounds for interventions which may momentarily stabilise BP but have no appreciable short-term or long-term effects. Further studies are warranted for improved understanding of clinically relevant trends and outcomes.

Technical Skills Curriculum in Neonatology: A Modified European Delphi Study.

INTRODUCTION: Simulation-based training (SBT) aids healthcare providers in acquiring the technical skills necessary to improve patient outcomes and safety. However, since SBT may require significant resources, training all skills to a comparable extent is impractical. Hence, a strategic prioritization of technical skills is necessary. While the European Training Requirements in Neonatology provide guidance on necessary skills, they lack prioritization. We aimed to identify and prioritize technical skills for a SBT curriculum in neonatology. METHODS: A three-round modified Delphi process of expert neonatologists and neonatal trainees was performed. In round one, the participants listed all the technical skills newly trained neonatologists should master. The content analysis excluded duplicates and non-technical skills. In round two, the Copenhagen Academy for Medical Education and Simulation Needs Assessment Formula (CAMES-NAF) was used to preliminarily prioritize the technical skills according to frequency, importance of competency, SBT impact on patient safety, and feasibility for SBT. In round three, the participants further refined and reprioritized the technical skills. Items achieving consensus (agreement of ≥75%) were included. RESULTS: We included 168 participants from 10 European countries. The response rates in rounds two and three were 80% (135/168) and 87% (117/135), respectively. In round one, the participants suggested 1964 different items. Content analysis revealed 81 unique technical skills prioritized in round two. In round three, 39 technical skills achieved consensus and were included. CONCLUSION: We reached a European consensus on a prioritized list of 39 technical skills to be included in a SBT curriculum in neonatology.

Increased Survival Concomitant with Unchanged Morbidity and Cognitive Disability among Infants Born at the Limit of Viability before 24 Gestational Weeks in 2009-2019.

INTRODUCTION: The aim was to determine risk factors among mothers and outcomes for their children born at the limit of viability in 2009-2019, before and after the introduction of extended interventionist guidelines. METHODS: A retrospective cohort study of births at 22 + 0-23 + 6 gestational weeks in a Swedish Region in 2009-2015 (n = 119), as compared to 2016-2019 (n = 86) after the introduction of new national interventionist guidelines. Infant mortality, morbidity, and cognitive functions at 2 years corrected age according to the Bayley-III Screening Test were monitored. RESULTS: Maternal risk factors for extreme preterm birth were identified. The intrauterine fetal death rates were comparable. Among births at 22 weeks, the neonatal mortality tended to decrease (96 vs. 76% of live births (p = 0.05)), and the 2-year survival tended to increase (4 vs. 24% (p = 0.05)). Among births at 23 weeks, the neonatal mortality decreased (56 vs. 27% of live births (p = 0.01)), and the 2-year survival increased (42 vs. 64% (p = 0.03)). Somatic morbidity and cognitive disability at 2 years corrected age were unchanged. CONCLUSION: We identified maternal risk factors that emphasize the need for standardized follow-up and counseling for women at increased risk of preterm birth at the limit of viability. The increased infant survival concomitant with unchanged morbidity and cognitive disability highlight the importance of ethical considerations regarding interventionist approaches at threatening preterm birth before 24 weeks.

Hyper high haemoglobin content in red blood cells and erythropoietic transitions postnatally in infants of 22 to 26 weeks' gestation: a prospective cohort study.

OBJECTIVE: Blood cell populations, including red blood cells (RBC) unique to the extremely preterm (EPT) infant, are potentially lost due to frequent clinical blood sampling during neonatal intensive care. Currently, neonatal RBC population heterogeneity is not described by measurement of total haemoglobin or haematocrit. We therefore aimed to describe a subpopulation of large RBCs with hyper high haemoglobin content, >49 pg (Hyper-He) following EPT birth. DESIGN: Prospective observational cohort study. SETTING: Two Swedish study centres. PARTICIPANTS: Infants (n=62) born between gestational weeks 22+0 to 26+6. METHODS: Prospective data (n=280) were collected from March 2020 to September 2022 as part of an ongoing randomised controlled trial. Blood was sampled from the umbilical cord, at postnatal day 1-14, 1 month, 40 weeks' postmenstrual age and at 3 months' corrected age. RESULTS: At birth, there was a considerable inter-individual variation; Hyper-He ranging from 1.5% to 24.9% (median 7.0%). An inverse association with birth weight and gestational age was observed; Spearman's rho (CI) -0.38 (-0.63 to -0.07) and -0.39 (-0.65 to -0.05), respectively. Overall, Hyper-He rapidly decreased, only 0.6%-5.0% (median 2.2%) remaining 2 weeks postnatally. Adult levels (<1%) were reached at corresponding term age. CONCLUSION: Our results point to gestational age and birth weight-dependent properties of the RBC population. Future work needs to verify results by different measurement techniques and elucidate the potential role of differing properties between endogenous and transfused RBCs in relation to neonatal morbidities during this important time frame of child development. TRIAL REGISTRATION NUMBER: NCT04239690.

[Survival and prematurity-related neonatal diagnoses among children born before 24 gestational weeks in Sweden 2007-2018]. / Allt fler barn födda före vecka 24 överlever, men sjukligheten är hög.

Children born before 24 gestational weeks had high neonatal morbidity and a majority had one or more neurodevelopmental disorders in addition to somatic diagnoses in childhood. Active Swedish perinatal care of infants with gestational age <24 weeks has resulted in a survival rate of more than 50 percent. Resuscitation of these immature infants is controversial, and some countries offer comfort care only. In a retrospective review of medical files and registries of 399 Swedish infants born before 24 gestational weeks, a majority had severe prematurity-related neonatal diagnoses. In childhood (2-13 years), 75 percent had at least one neurodevelopmental disorder and 88 percent had one or more prematurity-related somatic diagnosis (permanent or transient) that was likely to affect their quality of life. Long-term consequences for surviving infants should be considered in general recommendations as well as in parental information.

Neonatal Morbidities and Feeding Tolerance Outcomes in Very Preterm Infants, before and after Introduction of Probiotic Supplementation.

While probiotics are reported to reduce the risks of neonatal morbidities, less is known about probiotics and feeding tolerance. With this retrospective cohort study, we investigate whether introduction of probiotic supplementation as the standard of care was associated with fewer neonatal morbidities and improved feeding tolerance in very preterm infants. Using the Swedish Neonatal Quality Register, 345 live-born very preterm infants (28-31 weeks' gestation), from January 2019-August 2021, in NICUs in Stockholm, Sweden, either received probiotic supplementation (Bifidobacterium infantis, Bifidobacterium lactis, Streptococcusthermophilus) (139) or no supplementation (206); they were compared regarding a primary composite outcome of death, sepsis, and/or necrotising enterocolitis and secondary outcomes: time to full enteral feeding and antibiotics use. Probiotics seemed associated with a reduced risk of the composite outcome (4.3% versus 9.2%, p = 0.08). In the subgroup of 320 infants without the primary outcome, probiotics were associated with shorter time to full enteral feeding (6.6 days versus 7.2 days) and less use of antibiotics (5.2 days versus 6.1 days). Our findings suggest that probiotics improve feeding tolerance and further support that very preterm infants may benefit from probiotic supplementation.

Retrospective evaluation of ophthalmological and neurological outcomes for infants born before 24 weeks gestational age in a Swedish cohort.

OBJECTIVES: To retrospectively evaluate ophthalmological and neurological outcomes in a Swedish cohort of infants born before 24 weeks gestational age (GA) and explore risk factors for visual impairment. SETTING: Eye and paediatric clinics in Sweden. PARTICIPANTS: Infants screened for retinopathy of prematurity (ROP) (n=399), born before 24 weeks GA, 2007-2018. Cases were excluded if ophthalmological follow-up records could not be traced. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were ophthalmological, including visual acuity (VA), refractive error, strabismus, nystagmus and cerebral visual impairment (CVI). Secondary outcomes comprised neonatal and neurological morbidities. Data were retrospectively retrieved from medical records. RESULTS: The 355 assessed children had a median GA of 23 weeks and 2 days and a median birth weight of 565 g. At the last available ophthalmological examination, the median age was 4.8 years (range 0.5-13.2 years). Nystagmus was recorded in 21.1%, strabismus in 34.8%, and 51.0% wore spectacles. Seventy-three of 333 (21.9%) were visually impaired, defined as being referred to a low vision clinic and/or having a VA less than 20/60 at 3.5 years of age or older. ROP treatment was a significant risk factor for visual impairment (OR 2.244, p=0.003). Visually impaired children, compared with children without visual impairment, more often had neurological deficits such as intellectual disability 63.8% versus 33.3% (p<0.001), epilepsy 21.1% versus 7.5% (p=0.001) and autism spectrum disorders 32.8% versus 20.9% (p=0.043). Nine of the 355 children had been diagnosed with CVI. CONCLUSIONS: Children born before 24 weeks GA frequently had visual impairment in association with neurological deficits. CVI was rarely diagnosed. A multidisciplinary approach for the evaluation and habilitation of these vulnerable infants is warranted. National follow-up guidelines need to be developed and implemented.

National cohort of infants born before 24 gestational weeks showed increased survival rates but no improvement in neonatal morbidity.

AIM: To describe survival and neonatal morbidities in infants born before 24 weeks of gestation during a 12-year period. METHODS: Data were retrieved from national registries and validated in medical files of infants born before 24 weeks of gestation 2007-2018 in Sweden. Temporal changes were evaluated. RESULTS: In 2007-2018, 282 live births were recorded at 22 weeks and 460 at 23 weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23 weeks increased from 20% to 38% (p = 0.006) and from 45% to 67% (p < 0.001) respectively. Caesarean section increased from 12% to 22% (p = 0.038) for infants born at 22 weeks. Neonatal morbidity rates in infants alive at 40 weeks of postmenstrual age (n = 399) were unchanged except for an increase in necrotising enterocolitis from 0 to 33% (p = 0.017) in infants born at 22 weeks of gestation. Bronchopulmonary dysplasia was more common in boys than girls, 90% versus 82% (p = 0.044). The number of infants surviving to 40 weeks doubled over time. CONCLUSION: Increased survival of infants born before 24 weeks of gestation resulted in increasing numbers of very immature infants with severe neonatal morbidities likely to have a negative impact on long-term outcome.

Neurodevelopmental disorders and somatic diagnoses in a national cohort of children born before 24 weeks of gestation.

AIM: This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. METHODS: Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. RESULTS: We studied 383 children born at a median of 23.3 (range 21.9-23.9) weeks, with a median birthweight of 565 (range 340-874) grams. Three-quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). CONCLUSION: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.

Kidney volume, kidney function, and ambulatory blood pressure in children born extremely preterm with and without nephrocalcinosis.

BACKGROUND: Reduced kidney volume (KV) following prematurity is a proxy for reduced nephron number and is associated with the development of hypertension and end-stage renal disease in adults. We investigated whether extreme prematurity affects KV, function, and blood pressure in school-aged children and if nephrocalcinosis (NC) developed during the neonatal period had additional effects. METHODS: We investigated 60 children at a mean age of 7.7 years: 20 born extremely preterm (EPT < 28 weeks gestational age with NC (NC+)), 20 born EPT without NC (NC-), and 19 born as full-term infants (control). We measured KV by ultrasound, collected blood and urine samples to evaluate renal function, and measured office and 24-h ambulatory blood pressure (ABPM). RESULTS: Children born EPT had significantly smaller kidneys (EPT (NC+ NC-) vs control (estimated difference, 11.8 (CI - 21.51 to - 2.09 ml), p = 0.018) and lower but normal cystatin C-based glomerular filtration rate compared with control (estimated difference, - 10.11 (CI - 0.69 to - 19.5), p = 0.035). KV and function were not different between NC+ and NC- groups. Change in KV in relation to BSA (KV/BSA) from the neonatal period to school age showed significantly more EPT children with neonatal NC having a negative evolution of KV (p = 0.01). Blood pressure was normal and not different between the 3 groups. Fifty percent of EPT had a less than 10% day-to-night decline in ABPM. CONCLUSIONS: Kidney growth and volume is affected by EPT birth with NC being a potential aggravating factor. Circadian blood pressure regulation seems abnormal in EPT-born children.

Decreased heart rate variability in children born with low birth weight.

BACKGROUND: Low birth weight (LBW) is associated with cardiovascular morbidity in adulthood. Imbalance in the autonomic nervous system (ANS) has been implicated as a mechanism behind the developmental programming of cardiovascular function. We hypothesized that deviations in the ANS function are seen in children born with LBW. METHODS: Eighty-six children were included: 31 born preterm (<32 wk gestational age), 27 born at term but small for gestational age (SGA), and 28 born at term with normal birth weight (control). Twenty-four-hour Holter-electrocardiogram monitoring was performed at an average age of 9 y. Heart rate variability results were analyzed using frequency and time domain methods. RESULTS: All frequency components and both time domain parameters tested were significantly lower in the preterm and SGA children compared with controls. The low frequency/high frequency ratio was not significantly different between children born with LBW and controls. CONCLUSION: The autonomic control appears to be affected in children born with LBW despite gestational age at birth. Decreased total power, as an estimation of the ANS's global activity, rather than the balance between parasympathetic and sympathetic modulation might be an early marker of cardiovascular disease later on in life for LBW born children.

Differences in insulin resistance markers between children born small for gestational age or born preterm appropriate for gestational age.

AIM: To evaluate the impact of prenatal or postnatal compromised environment on glucose homoeostasis in children born preterm and appropriate for gestational age or small for gestational age (SGA) at term. METHOD: Seventy-seven children (median 9.9 years, range 8.5-10) born at Karolinska Hospital were allocated to three groups: 21 subjects born before 30 weeks of gestational age (preterm), 26 SGA at term and 30 at term with appropriate birth weight (control). Anthropometric measurements were taken, and fasting blood samples for haemoglobin A1c, glucose, insulin, IGFBP-1, IGF-1 and lipid profile were taken. Glucose, insulin and IGFBP-1 samples were taken at 0, 30 and 120 min during an oral glucose tolerance test (OGTT). RESULTS: Subjects born preterm or SGA were shorter and thinner compared with Controls. After adjustment for body mass index (BMI), the SGA group had higher basal insulin levels (p = 0.029), higher homoeostasis model assessment-insulin resistance (p = 0.012) and lower whole-body insulin sensitivity index (p = 0.007) than Controls. IGFBP-1 decrease during OGTT was attenuated in the Preterm group compared with the Control (p = 0.045) and SGA groups (p = 0.007). CONCLUSION: The higher fasting insulin level in the SGA children, adjusted for BMI, could indicate peripheral insulin resistance. Preterm born children had reduced suppression of IGFBP-1 during OGTT, suggesting hepatic insulin resistance.

Renal volume and function in school-age children born preterm or small for gestational age.

Impaired renal development during foetal life is a proposed mechanism for adult hypertension in people born small. Whether preterm birth contributes to such adverse development is still unclear. We investigated the selective contributions from foetal growth restriction or preterm birth to renal function and volume in children with low birth weight. Three groups of 9 to 12-year-old children were studied: those born at < 32 gestational weeks (preterm, n = 39), those born at term but small for gestational age (SGA, n = 29) and those born at the term appropriate for gestational age (controls, n = 37). We estimated renal function by calculating glomerular filtration rate (GFR) and by measuring urinary proteins. Volumetric ultrasound of the kidneys was performed in 86 children (preterm, n = 33; SGA, n = 25; controls, n = 29). Estimated glomerular filtration rate (eGFR) and urinary protein patterns were similar between the groups. Kidney volume (preterm 162 ml (31); SGA 163 ml (26) and controls 182 ml (47)) was smaller in the preterm group than in the controls, but the difference was not significant when adjusted for body surface area, gender and age (P = 0.25). Total renal volume correlated to birth weight (r = 0.23, P = 0.03). No significant differences were found in renal function or volume between the three groups at school age.

Low-dose danaparoid sodium catheter flushes in an intensive care infant suffering from heparin-induced thrombocytopenia.

OBJECTIVE: Despite controversy about whether peripheral and central venous catheters should be locked with heparin to prevent catheter-associated clotting, the practice is widespread. We describe a severe side effect of the practice: a case of heparin-induced thrombocytopenia occurring with catheter flushes using unfractionated heparin (UFH) in a 10-month-old boy successfully treated with danaparoid. Patient: A preterm-born patient (33 wks gestational age, birth weight 1200 g) suffering from VACTERL syndrome was repeatedly treated with UFH in the context of several invasive procedures. On day 310 of age, a central venous catheter was inserted to provide total parenteral nutrition. The central catheter was flushed with a continuous infusion of UFH at 100 U/day, and a decrease in platelet counts from 150,000/&mgr;L (on day 310 of age) to 45,000/&mgr;L (on day 319 of age) was observed. Clinically suspected heparin-induced thrombocytopenia (HIT) was serologically confirmed by demonstrating HIT antibodies with platelet factor 4/heparin complex specificity. Main Result: Catheter flushing was switched to low-dose danaparoid sodium as a continuous infusion at 15 anti-factor Xa units per day. Two days later, platelet counts recovered. Neither catheter thrombosis nor systemic thromboembolic complications occurred during the follow up period. CONCLUSIONS: Even continuous infusion of low-dose heparin to provide patency of central venous port catheters may trigger the primary immune response of HIT. Low-dose danaparoid sodium, a heparinoid, can prevent in-catheter thrombus formation and allows normalization of platelet counts in acute HIT.