Recurrent Late-Onset Sepsis in Extremely Low Birth Weight Infants Is Associated with Motor Deficits in Early School Age.

INTRODUCTION: Sepsis is regarded as a risk factor for brain injury in preterm infants. We herein hypothesize that extremely low birth weight infants (ELBWI, birth weight <1,000 g) having survived recurrent blood culture-proven late-onset sepsis (LOS) episodes are more likely to have an adverse long-term neurologic outcome. METHODS: In a large multicenter observational study of ELBWI ≤28 6/7 weeks, we evaluated the impact of recurrent LOS (blood culture-proven, after day 7 of life) on development at 5-6 years. Neurodevelopment, behavior, and motor qualities were tested by blinded investigators. Univariate and logistic regression analyses were performed. RESULTS: The cohort consisted of 1343 ELBWI including 1,080 infants without LOS, 186 infants with one LOS, and 77 with recurrent LOS, i.e., 55 infants with two and 22 infants with three LOS episodes. After Bonferroni-Holm correction, multiple logistic regression analysis revealed recurrent sepsis to be significantly associated with adverse motor development (critical MABC-2 testing: 3.3 [1.5-7.3], p = 0.003, pB = 0.012), whereas no significant impact of recurrent LOS was found on intelligence quotient and behavioral difficulties. Odds of having critical motor testing results for infants with recurrent LOS were 1.7 times (95% confidence interval 1.4-2.3) that of infants with one LOS. CONCLUSION: Recurrent sepsis in preterm infants is associated with adverse long-term motor development. However, infants with recurrent infections are also more likely to have preterm-related complications, and reasons for a worse neurodevelopmental outcome remain to be elucidated.

Sleep problems in infancy and early school age in very preterm infants.

BACKGROUND: Sleep plays an important role for psychological and physical health, especially in infants at high risk for long-term neurodevelopmental impairment such as preterm infants. OBJECTIVE: Our study aimed at determining risk factors for long-term sleep impairment in very-preterm (VPT; <32 weeks of gestation) infants. METHODS: Sleep problems were analyzed in an observational study in infants of the German Neonatal Network born between January 1st 2009 and December 31st 2014. Parental questionnaires of n = 2928 VPT children were evaluated regarding the child's sleep behavior at five years of age. Univariate and logistic regression analyses were used to identify risk factors for delayed sleep onset and hyperactivity/inattention (Strength and Difficulties Questionnaire). In a second cohort of n = 342 VPT infants, sleep habits were evaluated at toddlers age via the Infant Sleep Questionnaire. RESULTS: In our cohorts, 424/2928 (14.5 %) preterm children were diagnosed with delayed sleep onset at early school age while 57/342 (16.7 %) had sleep impairment in early infancy. Gestational age was not independently associated with sleep problems (i.e., early school age: OR 0.97, 95 % CI 0.9-1.1, p = 0.15). Notably, in both our cohorts, neonatal exposure to analgesics and sedatives was associated with a higher risk for sleep problems, i.e., early school age: exposure to sedatives: OR 1.31, 95%CI 1.02-1.7, p = 0.03. Sleep problems and drug exposure were both associated with hyperactivity/inattention. CONCLUSION: Sleep problems of VPT children are unrelated to gestational age which suggests rather individual risk factors. The significant neonatal exposure to analgesics and sedatives may contribute to long-term sleep impairment.

Infants Younger Than 90 Days Admitted for Late-Onset Sepsis Display a Reduced Abundance of Regulatory T Cells.

Objective: To provide epidemiological data of infants < 90 days of age with suspected late-onset sepsis (LOS) and evaluate distinct immunological specificities. We hypothesized that previously healthy infants < 3 months of age with sepsis have a yet undefined immunological predisposition; e.g. differences in lymphocyte subsets including regulatory T cells. Methods: We performed an exploratory, single center study between January 1st, 2019 and June 1st, 2021. Routine diagnostics included conventional culture (blood, cerebrospinal fluid, urine), PCR and inflammatory markers in infants < 90 days of age with suspected sepsis. We additionally analyzed lymphocyte subsets and CD4+ CD25+ forkhead box protein (FoxP3)+ Tregs at admission for sepsis workup as compared to age-matched controls. Results: A convenience sample cohort of n= 51 infants with sepsis workup was enrolled. Invasive bacterial infection (IBI) was diagnosed in 25 (49.0%) patients including two infants with a rhinovirus co-infection and viral infection in 14 (27.5%) neonates. No infectious cause was found in 12 cases. Infants with suspected LOS displayed a decreased abundance of CD4+ FoxP3+ T cells as compared to controls, which was most pronounced in the subgroup of infants with IBI. We also noticed elevated HLA-DR-positive CD3+ cells in infants with LOS and a higher CD4/CD8-ratio in infants with viral infection as compared to healthy controls. Infants with viral infections had a higher number of natural killer cells as compared to infants with IBI. Conclusion: Our exploratory data support the concept of a potential immaturity state and failed immune tolerance development for young infants with LOS. Future large-scale studies are needed to elucidate pre-sepsis conditions and to target the microbiome-immunity interplay as a potential risk pattern.

Five Year Follow Up of Extremely Low Gestational Age Infants after Timely or Delayed Administration of Routine Vaccinations.

This study is aimed at detecting the rate of untimely immunization in a large cohort of extremely low gestational age neonates (ELGANs) of the German Neonatal Network (GNN) and at addressing risk factors for delayed vaccination and associated long-term consequences. We performed an observational study of the GNN between 1st January 2010 and 31st December 2019. The immunization status for the hexavalent and pneumococcal immunization was evaluated in n = 8401 preterm infants <29 weeks of gestation. Univariate analysis and logistic/linear regression models were used to identify risk factors for vaccination delay and outcomes at a 5-year follow-up. In our cohort n = 824 (9.8%) ELGANs did not receive a timely first immunization with the hexavalent and pneumococcal vaccine. Risk factors for delayed vaccination were SGA status (18.1% vs. 13.5%; OR 1.3; 95% CI: 1.1-1.7), impaired growth and surrogates for complicated clinical courses (i.e., need for inotropes, necrotizing enterocolitis). At 5 years of age, timely immunized children had a lower risk of bronchitis (episodes within last year: 27.3% vs. 37.7%; OR 0.60, 95% CI: 0.42-0.86) but spirometry measures were unaffected. In conclusion, a significant proportion of ELGANs are untimely immunized, specifically those with increased vulnerability, even though they might particularly benefit from the immune-promoting effects of a timely vaccination.

Breastfeeding for 3 Months or Longer but Not Probiotics Is Associated with Reduced Risk for Inattention/Hyperactivity and Conduct Problems in Very-Low-Birth-Weight Children at Early Primary School Age.

(1) Background: We aimed to evaluate the effect of proposed "microbiome-stabilising interventions", i.e., breastfeeding for ≥3 months and prophylactic use of Lactobacillus acidophilus/ Bifidobacterium infantis probiotics on neurocognitive and behavioral outcomes of very-low-birthweight (VLBW) children aged 5-6 years. (2) Methods: We performed a 5-year-follow-up assessment including a strength and difficulties questionnaire (SDQ) and an intelligence quotient (IQ) assessment using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III test in preterm children previously enrolled in the German Neonatal Network (GNN). The analysis was restricted to children exposed to antenatal corticosteroids and postnatal antibiotics. (3) Results: 2467 primary school-aged children fulfilled the inclusion criteria. In multivariable linear regression models breastfeeding ≥3 months was associated with lower conduct disorders (B (95% confidence intervals (CI)): -0.25 (-0.47 to -0.03)) and inattention/hyperactivity (-0.46 (-0.81 to -0.10)) as measured by SDQ. Probiotic treatment during the neonatal period had no effect on SDQ scores or intelligence. (4) Conclusions: Prolonged breastfeeding of highly vulnerable infants may promote their mental health later in childhood, particularly by reducing risk for inattention/hyperactivity and conduct disorders. Future studies need to disentangle the underlying mechanisms during a critical time frame of development.

Preterm birth and sustained inflammation: consequences for the neonate.

Almost half of all preterm births are caused or triggered by an inflammatory process at the feto-maternal interface resulting in preterm labor or rupture of membranes with or without chorioamnionitis ("first inflammatory hit"). Preterm babies have highly vulnerable body surfaces and immature organ systems. They are postnatally confronted with a drastically altered antigen exposure including hospital-specific microbes, artificial devices, drugs, nutritional antigens, and hypoxia or hyperoxia ("second inflammatory hit"). This is of particular importance to extremely preterm infants born before 28 weeks, as they have not experienced important "third-trimester" adaptation processes to tolerate maternal and self-antigens. Instead of a balanced adaptation to extrauterine life, the delicate co-regulation between immune defense mechanisms and immunosuppression (tolerance) to allow microbiome establishment is therefore often disturbed. Hence, preterm infants are predisposed to sepsis but also to several injurious conditions that can contribute to the onset or perpetuation of sustained inflammation (SI). This is a continuing challenge to clinicians involved in the care of preterm infants, as SI is regarded as a crucial mediator for mortality and the development of morbidities in preterm infants. This review will outline the (i) role of inflammation for short-term consequences of preterm birth and (ii) the effect of SI on organ development and long-term outcome.

Lactobacillus Acidophilus/Bifidobacterium Infantis Probiotics Are Beneficial to Extremely Low Gestational Age Infants Fed Human Milk.

Objective: To evaluate the nutrition-related effects of prophylactic Lactobacillus acidophilus/Bifidobacterium infantis probiotics on the outcomes of preterm infants <29 weeks of gestation that receive human milk and/or formula nutrition. We hypothesize that human-milk-fed infants benefit from probiotics in terms of sepsis prevention and growth. METHODS: We performed an observational study of the German Neonatal Network (GNN) over a period of six years, between 1 January, 2013 and 31 December, 2018. Prophylactic probiotic use of L. acidophilus/B. infantis was evaluated in preterm infants <29 weeks of gestation (n = 7516) in subgroups stratified to feeding type: (I) Exclusively human milk (HM) of own mother and/or donors (HM group, n = 1568), (II) HM of own mother and/or donor and formula (Mix group, n = 5221), and (III) exclusive exposure to formula (F group, n = 727). The effect of probiotics on general outcomes and growth was tested in univariate models and adjusted in linear/logistic regression models. RESULTS: 5954 (76.5%) infants received L. acidophilus/B. infantis prophylactically for the prevention of necrotizing enterocolitis (NEC). Probiotic use was associated with improved growth measures in the HM group (e.g., weight gain velocity in g/day: effect size B = 0.224; 95% CI: 2.82-4.35; p < 0.001) but not in the F group (effect size B = -0.06; 95% CI: -3.05-0.28; p = 0.103). The HM group had the lowest incidence of clinical sepsis (34.0%) as compared to the Mix group (35.5%) and the F group (40.0%). Only in the Mix group, probiotic supplementation proved to be protective against clinical sepsis (OR 0.69; 95% CI: 0.59-0.79; p < 0.001). CONCLUSION: Our observational data indicate that the exposure to L. acidophilus/B. infantis probiotics may promote growth in exclusively HM-fed infants as compared to formula-fed infants. To exert a sepsis-preventive effect, probiotics seem to require human milk.

Efficacy of Bifidobacterium longum, B. infantis and Lactobacillus acidophilus probiotics to prevent gut dysbiosis in preterm infants of 28+0-32+6 weeks of gestation: a randomised, placebo-controlled, double-blind, multicentre trial: the PRIMAL Clinical Study protocol.

INTRODUCTION: The healthy 'eubiosis' microbiome in infancy is regarded as the microbiome derived from term, vaginally delivered, antibiotic free, breastfed infants at 4-6 months. Dysbiosis is regarded as a deviation from a healthy state with reduced microbial diversity and deficient capacity to control drug-resistant organisms. Preterm infants are highly sensitive to early gut dysbiosis. Latter has been associated with sepsis and necrotising enterocolitis, but may also contribute to long-term health problems. Probiotics hold promise to reduce the risk for adverse short-term outcomes but the evidence from clinical trials remains inconclusive and none has directly assessed the effects of probiotics on the microbiome at high resolution. METHODS AND ANALYSIS: A randomised, double blind, placebo-controlled study has been designed to assess the safety and efficacy of the probiotic mix of Bifidobacterium longum and infantis and Lactobacillus acidophilus in the prevention of gut dysbiosis in preterm infants between 28+0 and 32+6 weeks of gestation. The study is conducted in 18 German neonatal intensive care units. Between April 2018 and March 2020, 654 preterm infants of 28+0-32+6 weeks of gestation will be randomised in the first 48 hours of life to 28 days of once daily treatment with either probiotics or placebo. The efficacy endpoint is the prevention of gut dysbiosis at day 30 of life. A compound definition of gut dysbosis is used: (1) colonisation with multidrug-resistant organisms or gram-negative bacteria with high epidemic potential or (2) a significant deviation of the gut microbiota composition as compared with healthy term infants. Dysbiosis is determined by (1) conventional microbiological culture and (2) phylogenetic microbiome analysis by high-throughput 16S rRNA and metagenome sequencing. Persistence of dysbiosis will be assessed at 12-month follow-up visits. Side effects and adverse events related to the intervention will be recorded. Key secondary endpoint(s) are putative consequences of dysbiosis. A subgroup of infants will be thoroughly phenotyped for immune parameters using chipcytometry. ETHICS AND DISSEMINATION: Ethics approval was obtained in all participating sites. Results of the trial will be published in peer-review journals, at scientific meetings, on the website (www.primal-study.de) and via social media of parent organisations. TRIAL REGISTRATION NUMBER: DRKS00013197; Pre-results.

On Why Targets Evoke P3 Components in Prediction Tasks: Drawing an Analogy between Prediction and Matching Tasks.

P3 is the most conspicuous component in recordings of stimulus-evoked EEG potentials from the human scalp, occurring whenever some task has to be performed with the stimuli. The process underlying P3 has been assumed to be the updating of expectancies. More recently, P3 has been related to decision processing and to activation of established stimulus-response associations (S/R-link hypothesis). However, so far this latter approach has not provided a conception about how to explain the occurrence of P3 with predicted stimuli, although P3 was originally discovered in a prediction task. The present article proposes such a conception. We assume that the internal responses right or wrong both become associatively linked to each predicted target and that one of these two response alternatives gets activated as a function of match or mismatch of the target to the preceding prediction. This seems similar to comparison tasks where responses depend on the matching of the target stimulus with a preceding first stimulus (S1). Based on this idea, this study compared the effects of frequencies of first events (predictions or S1) on target-evoked P3s in prediction and comparison tasks. Indeed, frequencies not only of targets but also of first events had similar effects across tasks on target-evoked P3s. These results support the notion that P3 evoked by predicted stimuli reflects activation of appropriate internal "match" or "mismatch" responses, which is compatible with S/R-link hypothesis.

Effects on P3 of spreading targets and response prompts apart.

When key-press responses to targets have to be withheld until the presentation of response prompts, target-evoked P3 amplitudes are reduced and so is the P3 difference between rare and frequent targets (the oddball effect on P3). Recently we showed that this even applied when go-signals followed targets by 100ms. Here we aimed at replicating this result with more fine-grained temporal resolution in 100ms steps from 0ms to 500ms, and dissecting the P3 complex to stimulus- and response-related portions by applying residue iteration decomposition (RIDE). Frequent and rare target stimuli (in random series) were followed by go signals (and occasional no-go signals), with block-wise fixed stimulus-onset asynchronies (SOAs) from 0ms to 500ms. Target-evoked P3 amplitudes decreased monotonically across SOAs. Part of this decrease might have been due to an overlapping Contingent Negative Variation (CNV) prior to go signals, increasing across SOAs. When CNV was subtracted out by forming rare-frequent difference waveforms, oddball-P3 was largest at SOA 0, smallest at SOA 500, and equally large at SOAs 100-400. According to RIDE, it was P3's response-related part that was increased at SOA0. These results may be interpreted in terms of the stimulus-response-link reactivation hypothesis of P3.