Effects of extremely preterm birth on cytokine and chemokine responses induced by T-cell activation during infancy.

Objectives: Extremely preterm (EPT; gestational week < 28 + 0, < 1000 g) neonates are vulnerable to infections and necrotising enterocolitis, important contributors to mortality and morbidity. However, knowledge regarding their immune maturation remains limited. We here investigated the longitudinal development of functional T-cell capacity in EPT infants. Methods: Peripheral blood mononuclear cells were isolated at 14th and 28th day (D) and at gestational week 36 + 0 (Gw36) from EPT infants, participated in a randomised, double-blind, placebo-controlled study of Lactobacillus reuteri DSM 17938 probiotic supplementation. Blood collected from 25 full-term (FT) infants at D14 was used as control. The secretion of immune mediators was determined through comprehensive Luminex panels after stimulation with human T-cell activator CD3/CD28 beads. Results: The levels of many mediators were low in EPT infants at D14, whereas the secretion of several chemokines was higher in EPT than in FT infants. Furthermore, Th2:Th1 cytokine ratios were higher in EPT than in FT infants. Progressively elevated secretion of, for example, IFN-γ, TNF and IL-17A in EPT infants was observed from D14 to D28 and then at Gw36. Elevated levels were observed for many proinflammatory mediators at D28. Probiotic supplementation or perinatal factors (e.g. clinical chorioamnionitis, preeclampsia and delivery mode) did not influence the cytokine and chemokine responses. Conclusions: Immune mediators induced by T-cell activation in EPT infants were mainly reduced at D14 and Th2 skewed compared to those in FT infants, but mostly recovered at Gw36, indicating immune maturation. Increased proinflammatory responses at D28 may be related to the heightened risk of severe immune-associated complications seen in EPT infants.

Effect of human milk-based fortification in extremely preterm infants fed exclusively with breast milk: a randomised controlled trial.

Background: Mortality and severe morbidity remain high in extremely preterm infants. Human milk-based nutrient fortifiers may prevent serious complications and death. We aimed to investigate whether supplementation with human milk-based fortifier (HMBF), as compared to bovine milk-based fortifier (BMBF), reduced the incidence of the composite outcome of necrotising enterocolitis (NEC), sepsis, and mortality in extremely preterm infants exclusively fed human milk. Methods: In this multicentre, randomised controlled trial at 24 neonatal units in Sweden, extremely preterm infants born between gestational week 22 + 0 and 27 + 6 fed exclusively human breast milk (mother's own and/or donor milk), were randomly assigned (1:1) to receive targeted fortification with either HMBF or BMBF. Randomisation was conducted before the enteral feeds reached 100 mL/kg/day, and was stratified by enrolment site, gestational age, singleton/twin, and sex. The allocation was concealed before inclusion, but after randomisation the study was not blinded for the clinical staff. For the NEC diagnosis, the study group was masked to an independent radiologist, and the final assessment of NEC and culture-proven sepsis was done by a blinded consensus panel review. The primary outcome was the composite of NEC stage II-III, culture-proven sepsis, and mortality from inclusion to discharge, no longer than postmenstrual week 44 + 0, in the intention-to-treat population (ClinicalTrials.gov, NCT03797157). Findings: Between February 21st, 2019, and May 21st, 2021, 229 neonates were randomly assigned (115 HMBF, 114 BMBF). After exclusion of one infant due to parents' withdrawal of consent, 228 infants were included in the intention-to-treat analysis. Of the 115 infants assigned to HMBF, 41 (35.7%) fulfilled the criteria of either NEC, sepsis, or death, compared with 39 (34.5%) of 113 infants assigned to BMBF (OR 1.05, 95% CI 0.61-1.81, p = 0.86). Adverse events did not differ significantly between groups. Interpretation: Supplementation with HMBF, as compared with BMBF, did not reduce the incidence of the composite outcome of NEC, sepsis, or death. Our results do not support routine supplementation with HMBF as a nutritional strategy to prevent NEC, sepsis, or death in extremely preterm infants exclusively fed human milk. Funding: ALF grant, Prolacta Bioscience, Swedish Research Council, and Research Council for Southeast Sweden.

Factors associated with the increased incidence of necrotising enterocolitis in extremely preterm infants in Sweden between two population-based national cohorts (2004-2007 vs 2014-2016).

OBJECTIVE: To investigate potential risk factors behind the increased incidence of necrotising enterocolitis (NEC) in Swedish extremely preterm infants. DESIGN: Registry data from two population-based national cohorts were studied. NEC diagnoses (Bell stage ≥II) were validated against hospital records. PATIENTS: All liveborn infants <27 weeks of gestation 2004-2007 (n=704) and 2014-2016 (n=895) in Sweden. MAIN OUTCOME MEASURES: NEC incidence. RESULTS: The validation process resulted in a 28% reduction of NEC cases but still confirmed a higher NEC incidence in the later epoch compared with the earlier (73/895 (8.2%) vs 27/704 (3.8%), p=0.001), while the composite of NEC or death was lower (244/895 (27.3%) vs 229/704 (32.5%), p=0.022). In a multivariable Cox regression model, censored for mortality, there was no significant difference in early NEC (0-7 days of life) between epochs (HR=0.9 (95% CI 0.5 to 1.9), p=0.9), but being born in the later epoch remained an independent risk factor for late NEC (>7 days) (HR=2.7 (95% CI 1.5 to 5.0), p=0.001). In propensity score analysis, a significant epoch difference in NEC incidence (12% vs 2.8%, p<0.001) was observed only in the tertile of infants at highest risk of NEC, where the 28-day mortality was lower in the later epoch (35% vs 50%, p=0.001). More NEC cases were diagnosed with intramural gas in the later epoch (33/73 (45.2%) vs 6/26 (23.1%), p=0.047). CONCLUSIONS: The increase in NEC incidence between epochs was limited to cases occurring after 7 days of life and was partly explained by increased survival in the most extremely preterm infants. Misclassification of NEC is common.

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.

Mothers' experiences of a new early collaborative intervention, the EACI, in the neonatal period: A qualitative study.

AIM: To explore mothers' experiences of the EArly Collaborative Intervention. BACKGROUND: Preterm birth puts a considerable emotional and psychological burden on parents and families. Parents to moderate and late premature infants have shorter stays at the neonatal intensive care unit and have described a need for support. The EArly Collaborative Intervention was developed to support parents with preterm infants born between gestational Weeks 30 to 36. In this study, mothers' experiences of the new intervention were explored. DESIGN: A qualitative design guided by a reflexive thematic analysis according to Braun and Clarke. Interviews were individually performed with 23 mothers experienced with the EArly Collaborative Intervention. Data were identified, analysed and reported using reflexive thematic analysis. The COREQ checklist was used preparing the manuscript. RESULTS: Two main overarching themes were constructed. The first theme, 'mothers' feelings evoked from the EArly Collaborative Intervention' describes the emotions raised by the intervention and how the intervention affected their parental role. Their awareness of the preterm baby's behaviour increased, and the intervention helped the parents to communicate around their baby's needs. The second theme, 'based on the preterm baby's behavior', describes experiences of the provision and the learning process about their preterm baby's needs and communication. The intervention was experienced as helpful both immediately and for future interaction with the baby. CONCLUSIONS: Mothers found the intervention to be supportive and encouraging. They came to look upon their baby as an individual, and the new knowledge on how to care and interact with their baby affected both their own and their baby's well-being. Furthermore, the intervention felt strengthening for their relationship with the other parent. RELEVANCE TO CLINICAL PRACTICE: The EArly Collaborative Intervention can support parents' abilities as well as their relation to their baby and may thereby contribute to infant development, cognition and well-being.

Variations in the Composition of Human Milk Oligosaccharides Correlates with Effects on Both the Intestinal Epithelial Barrier and Host Inflammation: A Pilot Study.

BACKGROUND: Human milk oligosaccharides are complex, non-digestible carbohydrates that directly interact with intestinal epithelial cells to alter barrier function and host inflammation. Oligosaccharide composition varies widely between individual mothers, but it is unclear if this inter-individual variation has any impact on intestinal epithelial barrier function and gut inflammation. METHODS: Human milk oligosaccharides were extracted from the mature human milk of four individual donors. Using an in vitro model of intestinal injury, the effects of the oligosaccharides on the intestinal epithelial barrier and select innate and adaptive immune functions were assessed. RESULTS: Individual oligosaccharide compositions shared comparable effects on increasing transepithelial electrical resistance and reducing the macromolecular permeability of polarized (Caco-2Bbe1) monolayers but exerted distinct effects on the localization of the intercellular tight junction protein zona occludins-1 in response to injury induced by a human enteric bacterial pathogen Escherichia coli, serotype O157:H7. Immunoblots showed the differential effects of oligosaccharide compositions in reducing host chemokine interleukin 8 expression and inhibiting of p38 MAP kinase activation. CONCLUSIONS: These results provide evidence of both shared and distinct effects on the host intestinal epithelial function that are attributable to inter-individual differences in the composition of human milk oligosaccharides.

Nordic study on human milk fortification in extremely preterm infants: a randomised controlled trial-the N-forte trial.

INTRODUCTION: The mortality rate of extremely low gestational age (ELGA) (born

A protocol for characterization of extremely preterm infant gut microbiota in double-blind clinical trials.

16S rRNA gene sequencing enables microbial community profiling, but recovering fecal DNA from extremely premature infants is challenging. Here, we describe an optimized protocol for fecal DNA isolation, library preparation for 16S rRNA gene sequencing, taxonomy assignation, and statistical analyses. The protocol is complemented with a quantitative PCR for probiotic L. reuteri identification. This protocol describes how to characterize preterm infant gut microbiota and relate it to probiotic supplementation and clinical outcomes. It is customizable for other clinical trials. For complete details on the use and execution of this protocol, please refer to Martí et al. (2021) and Spreckels et al. (2021).

Extreme prematurity and sepsis strongly influence frequencies and functional characteristics of circulating γδ T and natural killer cells.

OBJECTIVES: Extremely low gestational age neonates with extremely low birthweight (ELGAN/ELBW) are highly susceptible to infection. This is linked to their relatively immature immune system which is not yet fully compatible with an extra-uterine environment. Here, we performed a longitudinal characterisation of unconventional T and natural killer (NK) cells in ELGAN/ELBW during their first months of life. METHODS: Peripheral blood mononuclear cells were collected from 97 ELGAN/ELBW at 14 and 28 days of life and at a time point corresponding to postmenstrual week 36 + 0. γδ T-cell, NKT-cell, mucosa-associated invariant T-cell and NK cell frequencies and characteristics were analysed by flow cytometry. As control, cells from 14-day-old full-term (FT) infants were included. RESULTS: Extreme prematurity had significant bearing on γδ T-cell and NK cell frequencies and characteristics. ELGAN/ELBW had significantly higher proportions of γδ T cells that were skewed towards effector and effector memory phenotypes, characteristics that were maintained throughout the study period. Expression of the gut homing receptor CCR9 was also more common in γδ T cells from ELGAN/ELBW. Conversely, NK cell frequencies were markedly lower and skewed towards a cytotoxic phenotype in the ELGAN/ELBW group at 14 days of age. Culture-proven sepsis with an onset during the first 14 days after birth further manifested these differences in the γδ T- and NK cell populations at 14 days of age. CONCLUSION: Prematurity strongly influences the levels of γδ T and NK cells, in particular in cases where sepsis debuts during the first 2 weeks of life.

Lactobacillus reuteri Colonisation of Extremely Preterm Infants in a Randomised Placebo-Controlled Trial.

Lactobacillus reuteri DSM 17938 supplementation reduces morbidities in very low birth weight infants (<1500 g), while the effect on extremely low birth weight infants (ELBW, <1000 g) is still questioned. In a randomised placebo-controlled trial (ClinicalTrials.gov ID NCT01603368), head growth, but not feeding tolerance or morbidities, improved in L. reuteri-supplemented preterm ELBW infants. Here, we investigate colonisation with the probiotic strain in preterm ELBW infants who received L. reuteri DSM 17938 or a placebo from birth to postmenstrual week (PMW) 36. Quantitative PCR was used on 582 faecal DNA samples collected from 132 ELBW infants at one, two, three, and four weeks, at PMW 36, and at two years of age. Human milk oligosaccharides were measured in 31 milk samples at two weeks postpartum. At least 86% of the ELBW infants in the L. reuteri group were colonised with the probiotic strain during the neonatal period, despite low gestational age, high antibiotic pressure, and independent of infant feeding mode. Higher concentrations of lacto-N-tetraose, sialyl-lacto-N-neotetraose c, and 6'-sialyllactose in mother's milk weakly correlated with lower L. reuteri abundance. Within the L. reuteri group, higher L. reuteri abundance weakly correlated with a shorter time to reach full enteral feeding. Female sex and L. reuteri colonisation improved head growth from birth to four weeks of age. In conclusion, L. reuteri DSM 17938 supplementation leads to successful colonisation in ELBW infants.

Effects of Lactobacillus reuteri supplementation on the gut microbiota in extremely preterm infants in a randomized placebo-controlled trial.

Extremely low birth weight (ELBW) infants often develop an altered gut microbiota composition, which is related to clinical complications, such as necrotizing enterocolitis and sepsis. Probiotic supplementation may reduce these complications, and modulation of the gut microbiome is a potential mechanism underlying the probiotic effectiveness. In a randomized, double-blind, placebo-controlled trial, we assessed the effect of Lactobacillus reuteri supplementation, from birth to post-menstrual week (PMW)36, on infant gut microbiota. We performed 16S amplicon sequencing in 558 stool samples from 132 ELBW preterm infants at 1 week, 2 weeks, 3 weeks, 4 weeks, PMW36, and 2 years. Probiotic supplementation results in increased bacterial diversity and increased L. reuteri abundance during the 1st month. At 1 week, probiotic supplementation also results in a lower abundance of Enterobacteriaceae and Staphylococcaceae. No effects were found at 2 years. In conclusion, probiotics may exert benefits by modulating the gut microbiota composition during the 1st month in ELBW infants.

Human Milk Oligosaccharides Protect against Necrotizing Enterocolitis by Activating Intestinal Cell Differentiation.

SCOPE: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency and currently the leading cause of mortality in preterm infants. Recent studies show that human milk oligosaccharides (HMOs) reduce the frequency and incidence of NEC; however, the molecular mechanisms for their protection are largely unexplored. METHODS AND RESULTS: To address this gap, a genome-wide profiling of the intestinal epithelial transcriptome in response to HMOs using RNA-sequencing is performed. It is found that HMOs alter the host transcriptome in 225 unique target genes pertaining to cell proliferation and differentiation, including upregulation of stem cell differentiation marker HMGCS2. To validate these results, differentiation in Caco-2Bbe1 (Caco-2) intestinal cells is verified by Alcian Blue staining and transepithelial electrical resistance (TER) recordings. Furthermore, an in vivo model of NEC is also employed whereby neonatal pups are gavage fed HMOs. Interestingly, HMOs-fed pups show enhanced cell MUC2 differentiation and HMGCS2 expression. CONCLUSIONS: These findings demonstrate HMOs protect against NEC in part by altering the differentiation of the crypt-villus axis. In addition, this study suggests that pooled HMOs directly induce a series of biological processes, which provide mechanistic insights to how HMOs protect the host intestine.

Pre- and postnatal Lactobacillus reuteri treatment alters DNA methylation of infant T helper cells.

BACKGROUND: Perinatal childhood exposures, including probiotic supplementation, may affect epigenetic modifications and impact on immune maturation and allergy development. The aim of this study was to assess the effects of pre- and postnatal Lactobacillus reuteri supplementation on DNA methylation in relation to immune maturation and allergy development. METHODS: DNA methylation patterns were investigated for allergy-related T helper subsets using a locus-specific method and at a genome-wide scale using the Illumina 450K array. From a randomised, double-blind, placebo-controlled allergy prevention trial with pre- and postnatal probiotic supplementation, CD4+ T helper cells were obtained at birth (from cord blood), and 12 and 24 months of age (total (placebo/probiotics); locus-specific method: CB = 32 (17/15), 12 months = 24 (9/15), 24 months = 35 (15/20); Illumina: CB = 19 (10/9), 12 months = 10 (6/4), 24 months = 19(11/8)). RESULTS: Comparing probiotics to placebo, the greatest genome-wide differential DNA methylation was observed at birth, where the majority of sites were hypomethylated, indicating transcriptional accessibility in the probiotic group. Bioinformatic analyses, including network analyses, revealed a module containing 91 genes, enriched for immune-related pathways such as chemotaxis, PI3K-Akt, MAPK and TGF-ß signalling. A majority of the module genes were associated with atopic manifestations (OR = 1.43, P = 2.4 × 10-6 ), and a classifier built on this model could predict allergy development (AUC = 0.78, P = 3.0 × 10e-3 ). Pathways such as IFN-γ signalling and T-cell activation were more hypermethylated at birth compared with later in life in both intervention groups over time, in line with DNA methylation patterns in the IFNG locus obtained by the locus-specific methodology. CONCLUSION: Maternal L. reuteri supplementation during pregnancy alters DNA methylation patterns in CD4+ T cells towards enhanced immune activation at birth, which may affect immune maturation and allergy development.

Allergy development is associated with consumption of breastmilk with a reduced microbial richness in the first month of life.

BACKGROUND: Early colonization with a diverse microbiota seems to play a crucial role for appropriate immune maturation during childhood. Breastmilk microbiota is one important source of microbes for the infant, transferred together with maternal IgA antibodies. We previously observed that allergy development during childhood was associated with aberrant IgA responses to the gut microbiota already at 1 month of age, when the IgA antibodies are predominantly maternally derived in breastfed infants. OBJECTIVE: To determine the microbial composition and IgA-coated bacteria in breastmilk in relation to allergy development in children participating in an intervention trial with pre- and post-natal Lactobacillus reuteri supplementation. METHODS: A combination of flow cytometric cell sorting and 16S rRNA gene sequencing was used to characterize the bacterial recognition patterns by IgA in breastmilk samples collected one month post-partum from 40 mothers whose children did or did not develop allergic and asthmatic symptoms during the first 7 years of age. RESULTS: The milk fed to children developing allergic manifestations had significantly lower bacterial richness, when compared to the milk given to children that remained healthy. Probiotic treatment influenced the breastmilk microbiota composition. However, the proportions of IgA-coated bacteria, the total bacterial load and the patterns of IgA-coating were similar in breastmilk between mothers of healthy children and those developing allergies. CONCLUSION: Consumption of breastmilk with a reduced microbial richness in the first month of life may play an important role in allergy development during childhood.

Characterization of the γδ T-cell compartment during infancy reveals clear differences between the early neonatal period and 2 years of age.

γδ T cells are unconventional T cells that function on the border of innate and adaptive immunity. They are suggested to play important roles in neonatal and infant immunity, although their phenotype and function are not fully characterized in early childhood. We aimed to investigate γδ T cells in relation to age, prematurity and cytomegalovirus (CMV) infection. Therefore, we used flow cytometry to characterize the γδ T-cell compartment in cord blood and peripheral blood cells from 14-day-, 2-year- and 5-year-old children, as well as in peripheral blood samples collected at several time points during the first months of life from extremely premature neonates. γδ T cells were phenotypically similar at 2 and 5 years of age, whereas cord blood was divergent and showed close proximity to γδ T cells from 14-day-old neonates. Interestingly, 2-year-old children and adults showed comparable Vδ2+ γδ T-cell functionality toward both microbial and polyclonal stimulations. Importantly, extreme preterm birth compromised the frequencies of Vδ1+ cells and affected the functionality of Vδ2+ γδ T cells shortly after birth. In addition, CMV infection was associated with terminal differentiation of the Vδ1+ compartment at 2 years of age. Our results show an adult-like functionality of the γδ T-cell compartment already at 2 years of age. In addition, we demonstrate an altered γδ T-cell phenotype early after birth in extremely premature neonates, something which could possible contribute to the enhanced risk for infections in this vulnerable group of children.

Extremely Preterm Infants Have Significant Alterations in Their Conventional T Cell Compartment during the First Weeks of Life.

Extremely preterm neonates are particularly susceptible to infections, likely because of severely impaired immune function. However, little is known on the composition of the T cell compartment in early life in this vulnerable population. We conducted a comprehensive phenotypic flow cytometry-based longitudinal analysis of the peripheral conventional T cell compartment of human extremely low gestational age neonates (ELGAN) with extremely low birth weight (ELBW; <1000 g) participating in a randomized placebo-controlled study of probiotic supplementation. PBMCs from ELGAN/ELBW neonates were collected at day 14, day 28, and postmenstrual week 36. Comparisons were made with full-term 14-d-old neonates. Total CD4+ and CD8+ T cell frequencies were markedly lower in the preterm neonates. The reduction was more pronounced among the CD8+ population, resulting in an increased CD4/CD8 ratio. The preterm infants were also more Th2 skewed than the full-term infants. Although the frequency of regulatory T cells seemed normal in the ELGAN/ELBW preterm neonates, their expression of the homing receptors α4ß7, CCR4, and CCR9 was altered. Notably, ELGAN/ELBW infants developing necrotizing enterocolitis before day 14 had higher expression of CCR9 in CD4+T cells at day 14. Chorioamnionitis clearly associated with reduced T regulatory cell frequencies and functional characteristics within the preterm group. Finally, probiotic supplementation with Lactobacillus reuteri did not impose any phenotypic changes of the conventional T cell compartment. In conclusion, notable immaturities of the T cell compartment in ELGAN/ELBW neonates may at least partially explain their increased susceptibility to severe immune-mediated morbidities.

[Preterm delivery: an overview on epidemiology, pathophysiology and consequences for the individual and the society]. / Förtidsbörd största perinatala problemet - 5,7 procent av graviditeter i Sverige slutar för tidigt, inte klarlagt varför ­ kostar miljardbelopp varje år.

Preterm delivery in Sweden constitutes 5.7 % of all deliveries, which is among the lowest rates in the world. There has not been any increase in the proportion of iatrogenic preterm deliveries during the last decades.The main hypothesis concerning the causality of preterm delivery is still that of the ascending infection from the vagina to the uterus and inflammation resulting in contractions, rupture of membranes and delivery. The mechanisms behind parturition at term are still elusive and this is also true for preterm delivery. The genetic contribution to preterm delivery is about 25-30 %. The first genes that are associated with preterm delivery and gestational duration have recently been published. Huge progress has been made in care of preterm born infants. Sweden has among the lowest rates of mortality and morbidity in the world, especially in the lowest gestational weeks. New modes of care, family-centered care and hospital-assisted home care, have empowered the parents and reduced the cost for care.

[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.

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.

Probiotics promoted head growth in extremely low birthweight infants in a double-blind placebo-controlled trial.

AIM: This study evaluated if oral supplementation with the probiotic bacterium Lactobacillus reuteri DSM 17938 improved enteral feeding tolerance and growth rates in extremely low birthweight (ELBW) infants. METHOD: A randomised, double-blind, placebo-controlled trial comprising 134 ELBW (<1000 g) infants born before gestational week 28 + 0. Daily supplementation of L. reuteri (1.25 × 108 bacteria/day) or placebo started within 3 days and continued until gestational week 36 + 0. Primary outcome was feeding tolerance and secondary outcome growth rate calculated as z-score development. RESULTS: Feeding tolerance was similar in the probiotic and placebo group. Time to full enteral feeds was 15 days in both groups. The z-score of the head circumference decreased in both groups from birth to day 28 of life, but it decreased less in the L. reuteri group compared to the placebo group: -1.2 SD (95% CI: -1.4 to -1.0) versus -1.7 SD (95% CI: -2.0 to -1.5; p = 0.001). Other growth parameters were similar in the study groups. CONCLUSION: Lactobacillus reuteri did not reduce time to reach full enteral feeds in ELBW infants. The L. reuteri supplemented infants, however, had a better growth rate of the head during the first month of life.