Bifidobacteria-mediated immune system imprinting early in life.

Immune-microbe interactions early in life influence the risk of allergies, asthma, and other inflammatory diseases. Breastfeeding guides healthier immune-microbe relationships by providing nutrients to specialized microbes that in turn benefit the host's immune system. Such bacteria have co-evolved with humans but are now increasingly rare in modern societies. Here we show that a lack of bifidobacteria, and in particular depletion of genes required for human milk oligosaccharide (HMO) utilization from the metagenome, is associated with systemic inflammation and immune dysregulation early in life. In breastfed infants given Bifidobacterium infantis EVC001, which expresses all HMO-utilization genes, intestinal T helper 2 (Th2) and Th17 cytokines were silenced and interferon ß (IFNß) was induced. Fecal water from EVC001-supplemented infants contains abundant indolelactate and B. infantis-derived indole-3-lactic acid (ILA) upregulated immunoregulatory galectin-1 in Th2 and Th17 cells during polarization, providing a functional link between beneficial microbes and immunoregulation during the first months of life.

Stereotypic Immune System Development in Newborn Children.

Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 µL of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.

Antisecretory factor in breastmilk is associated with reduced incidence of sepsis in preterm infants.

BACKGROUND: Antisecretory Factor (AF) is a protein present in breastmilk that regulates inflammatory processes. We aimed to investigate the level of AF in mothers' own milk (MOM) in relation to sepsis and other neonatal morbidities in preterm infants. METHODS: Samples of breastmilk and infant plasma were collected at 1, 4, and 12 weeks after birth from 38 mothers and their 49 infants born before 30 weeks gestation. AF-compleasome in MOM was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) and inflammatory markers in infant plasma by a panel of 92 inflammatory proteins. Neonatal treatments and outcomes were recorded. RESULTS: The level of AF in MOM week 1 was lower for infants with later sepsis compared to no sepsis (p = 0.005). Corrected for nutritional intake of MOM, higher levels of AF decreased the risk for sepsis, OR 0.24. AF in MOM week 1 was negatively correlated to inflammatory proteins in infant plasma week 4, markedly IL-8, which was also associated with infant sepsis. Overall, higher AF levels in MOM was associated with fewer major morbidities of prematurity. CONCLUSION: Mother's milk containing high levels of antisecretory factor is associated with reduced risk for sepsis and inflammation in preterm infants. IMPACT: High level of antisecretory factor (AF) in mothers' own milk is associated with less risk for later sepsis in preterm infants. Receiving mothers' milk with low AF levels during the first week after birth is correlated with more inflammatory proteins in infant's plasma 2-4 weeks later. Human breastmilk has anti-inflammatory properties, and antisecretory factor in mothers' own milk is a component of potential importance for infants born preterm. The findings suggest that food supplementation with AF to mothers of preterm infants to increase AF-levels in breastmilk may be a means to decrease the risk of inflammatory morbidities of prematurity.

Potential of neonatal organ donation and outcome after transplantation.

Organ transplantation is limited by access to suitable organs. Infant recipient waitlist mortality is increased due to the scarcity of size-matched organs. Neonatal organ donors have been proposed as an underutilized source of donor organs. However, the literature on the actual prevalence and outcome of neonatal organ donation and transplantation is fragmented and not well analyzed. This literature review aims to summarize the available literature on the potential of neonatal organ donation and to analyze published cases of neonatal organ transplantation. A systematic search of the Medline and Cochrane databases yielded 2964 articles, which were screened for eligibility. In total, 86 articles were considered eligible, of which 34 were included in the literature review: 8 articles describing the potential of neonatal organ donation programs, and 26 articles describing clinical transplantation. Current evidence suggests there is a large pool of potential neonatal organ donors. In contrast, the literature on neonatal organ donor utilization is sparse. However, case series of successful kidney, heart, liver, hepatocyte, and multivisceral transplantation using organs from neonatal donors are summarized. Although good posttransplant organ function was achieved, the use of neonatal organs is associated with increased risk of thrombosis in both kidney and liver transplantation. Neonatal organ donation is a promising alternative for expanding the current donor pool. Experience is limited, but reported patient and graft survival are acceptable and more research on the subject is warranted.

Hematopoietic cellular aging is not accelerated during the first 2 years of life in children born preterm.

BACKGROUND: Prematurity in itself and exposure to neonatal intensive care triggers inflammatory processes and oxidative stress, leading to risk for disease later in life. The effects on cellular aging processes are incompletely understood. METHODS: Relative telomere length (RTL) was measured by qPCR in this longitudinal cohort study with blood samples taken at birth and at 2 years of age from 60 children (16 preterm and 44 term). Viral respiratory infections the first year were evaluated. Epigenetic biological DNA methylation (DNAm) age was predicted based on methylation array data in 23 children (11 preterm and 12 term). RTL change/year and DNAm age change/year was compared in preterm and term during the 2 first years of life. RESULTS: Preterm infants had longer telomeres than term born at birth and at 2 years of age, but no difference in telomere attrition rate could be detected. Predicted epigenetic DNAm age was younger in preterm infants, but rate of DNAm aging was similar in both groups. CONCLUSIONS: Despite early exposure to risk factors for accelerated cellular aging, children born preterm exhibited preserved telomeres. Stress during the neonatal intensive care period did not reflect accelerated epigenetic DNAm aging. Early-life aging was not explained by preterm birth. IMPACT: Preterm birth is associated with elevated disease risk later in life. Preterm children often suffer from inflammation early in life. Stress-related telomere erosion during neonatal intensive care has been proposed. Inflammation-accelerated biological aging in preterm is unknown. We find no accelerated aging due to prematurity or infections during the first 2 years of life.

Successful treatment of a cohort of infants with neonatal diabetes using insulin pumps including data on genetics and estimated incidence.

AIM: Neonatal diabetes is rare, and treatment is challenging. We present aspects on treatment, genetics and incidence. METHOD: This was a prospective cohort study including all cases in our study area in Sweden. We compared with data from the National Diabetes Registry, the Neonatal Quality Register and the National Patient Register. RESULTS: In the 19-year study period January 1, 1998 to December 31, 2016, we treated seven infants, five of them boys. Six patients used a subcutaneous insulin pump, and the smallest patient started at a weight of 938 g. Most important was for the pump to deliver minute doses of insulin and the design of cannulas and tubing. All patients could stop insulin treatment at 17-145 days of age. One patient relapsed at age 4.5 years. Four patients used the insulin pump after discharge. A mutation was identified in five patients, and this included all patients born after 30 weeks of gestation. The incidence of neonatal diabetes was 2/1 00 000, higher than previously estimated for Europe. Similar but lower incidences were reported in the registries. CONCLUSION: Insulin pumps were safe in neonatal diabetes. All seven cases were transient. Neonatal diabetes was more common in our area than reported from Europe.

Changes in Antisecretory Factor in Human Milk During the Postpartum and Length of Gestation.

BACKGROUND: Preterm infants are more susceptible to inflammatory complications than term infants. Human milk contains numerous bioactive components protecting the newborn infant. Antisecretory factor, a protein regulating secretory and inflammatory processes by complex binding with complement factors, is present in human milk. RESEARCH AIMS: To describe antisecretory factor (1) in mother's own milk in term and preterm infants; and (2) in donor milk before and after Holder pasteurization. METHODS: The study was prospective, longitudinal, explorative, and descriptive. Antisecretory factor-compleasome was determined using sandwich enzyme-linked immunosorbent assay in longitudinal human milk samples over 12 weeks from mothers (N = 87) of term (n = 41) and of preterm (n = 46) infants and 20 anonymized donor human milk samples before and after Holder pasteurization. RESULTS: Antisecretory factor-compleasome was overall higher in colostrum versus mature milk (p < .001) and no difference was found in term or preterm colostrum (p = .82). In mature milk, compleasome was higher and more variable in the preterm group (p = .01). After Holder pasteurization, compleasome levels increased (p < .001). CONCLUSION: Antisecretory factor followed the pattern of other immunological factors with high levels in colostrum. After preterm birth, levels of antisecretory factor were higher and more variable in mature milk. Holder pasteurization did not degrade antisecretory factor, indicating preserved anti-inflammatory properties in donor human milk.

Case report: Fatal outcome of pyridoxine-dependent epilepsy presenting as respiratory distress followed by a circulatory collapse.

Pyridoxine-dependent epilepsy is a rare autosomal recessive disease usually associated with neonatal seizures that do not respond to common antiseizure medications but are controlled by pyridoxine administration. Because the symptoms can mimic common neonatal disorders, the diagnosis can be initially missed or delayed. We report a fatal case of a boy who was initially diagnosed with respiratory distress, birth asphyxia, and persistent pulmonary hypertension and whose condition rapidly deteriorated during the first day of life.

Procurement and Evaluation of Hepatocytes for Transplantation From Neonatal Donors After Circulatory Death.

Hepatocyte transplantation is a promising treatment for liver failure and inborn metabolic liver diseases, but progress has been hampered by a scarcity of available organs. Here, hepatocytes isolated from livers procured for a neonatal hepatocyte donation program within a research setting were assessed for metabolic function and suitability for transplantation. Organ donation was considered for infants who died in neonatal intensive care in the Stockholm region during 2015-2021. Inclusion was assessed when a decision to discontinue life-sustaining treatment had been made and hepatectomy performed after declaration of death. Hepatocyte isolation was performed by three-step collagenase perfusion. Hepatocyte viability, yield, and function were assessed using fresh and cryopreserved cells. Engraftment and maturation of cryopreserved neonatal hepatocytes were assessed by transplantation into an immunodeficient mouse model and analysis of the gene expression of phase I, phase II, and liver-specific enzymes and proteins. Twelve livers were procured. Median warm ischemia time (WIT) was 190 [interquartile range (IQR): 80-210] minutes. Median viability was 86% (IQR: 71%-91%). Median yield was 6.9 (IQR: 3.4-12.8) x106 viable hepatocytes/g. Transplantation into immunodeficient mice resulted in good engraftment and maturation of hepatocyte-specific proteins and enzymes. A neonatal organ donation program including preterm born infants was found to be feasible. Hepatocytes isolated from neonatal donors had good viability, function, and engraftment despite prolonged WIT. Therefore, neonatal livers should be considered as a donor source for clinical hepatocyte transplantation, even in cases with extended WIT.

Selective transfer of maternal antibodies in preterm and fullterm children.

Preterm newborns are more likely to suffer from infectious diseases at birth compared to children delivered at term. Whether this is due to compromised cellular, humoral, or organ-specific development remains unclear. To begin to define whether maternal-fetal antibody transfer profiles differ across preterm (PT) and fullterm (FT) infants, the overall quantity and functional quality of an array of 24 vaccine-, endemic pathogen-, and common antigen-specific antibodies were assessed across a cohort of 11 PT and 12 term-delivered maternal:infant pairs from birth through week 12. While total IgG levels to influenza, pneumo, measles, rubella, EBV, and RSV were higher in FT newborns, selective Fc-receptor binding antibodies was noted in PT newborns. In fact, near equivalent antibody-effector functions were observed across PT and FT infants, despite significant quantitative differences in transferred antibody levels. Moreover, temporal transfer analysis revealed the selective early transfer of FcRn, FcγR2, and FcγR3 binding antibodies, pointing to differential placental sieving mechanisms across gestation. These data point to selectivity in placental transfer at distinct gestational ages, to ensure that children are endowed with the most robust humoral immunity even if born preterm.

A Novel Association between YKL-40, a Marker of Structural Lung Disease, and Short Telomere Length in 10-Year-Old Children with Bronchopulmonary Dysplasia.

Extremely preterm infants are born with immature lungs and are exposed to an inflammatory environment as a result of oxidative stress. This may lead to airway remodeling, cellular aging and the development of bronchopulmonary dysplasia (BPD). Reliable markers that predict the long-term consequences of BPD in infancy are still lacking. We analyzed two biomarkers of cellular aging and lung function, telomere length and YKL-40, respectively, at 10 years of age in children born preterm with a history of BPD (n = 29). For comparison, these markers were also evaluated in sex-and-age-matched children born at term with childhood asthma (n = 28). Relative telomere length (RTL) was measured in whole blood with qPCR and serum YKL-40 with ELISA, and both were studied in relation to gas exchange and the regional ventilation/perfusion ratio using three-dimensional V/Q-scintigraphy (single photon emission computer tomography, SPECT) in children with BPD. Higher levels of YKL-40 were associated with shorter leukocyte RTL (Pearson's correlation: -0.55, p = 0.002), but were not associated with a lower degree of matching between ventilation and perfusion within the lung. Serum YKL-40 levels were significantly higher in children with BPD compared to children with asthma (17.7 vs. 13.2 ng/mL, p < 0.01). High levels of YKL-40 and short RTLs were associated to the need for ventilatory support more than 1 month in the neonatal period (p < 0.01). The link between enhanced telomere shortening in childhood and structural remodeling of the lung, as observed in children with former BPD but not in children with asthma at the age of 10 years, suggests altered lung development related to prematurity and early life inflammatory exposure. In conclusion, relative telomere length and YKL-40 may serve as biomarkers of altered lung development as a result of early-life inflammation in children with a history of prematurity.

The repertoire of maternal anti-viral antibodies in human newborns.

All circulating immunoglobulin G (IgG) antibodies in human newborns are of maternal origin1 and transferred across the placenta to provide passive immunity until newborn IgG production takes over 15 weeks after birth2. However, maternal IgG can also negatively interfere with newborn vaccine responses3. The concentration of IgG increases sharply during the third trimester of gestation and children delivered extremely preterm are believed to largely lack this passive immunity1,2,4. Antibodies to individual viruses have been reported5-12, but the global repertoire of maternal IgG, its variation in children, and the epitopes targeted are poorly understood. Here, we assess antibodies against 93,904 epitopes from 206 viruses in 32 preterm and 46 term mother-child dyads. We find that extremely preterm children receive comparable repertoires of IgG as term children, albeit at lower absolute concentrations and consequent shorter half-life. Neutralization of the clinically important respiratory syncytial virus (RS-virus) was also comparable until three months of age. These findings have implications for understanding infectious disease susceptibility, vaccine development, and vaccine scheduling in newborn children.

Palivizumab prophylaxis and hospitalization for respiratory syncytial virus disease in the Stockholm infant population, 1999 through 2002.

BACKGROUND: There are few independent, population-based reports that estimate the risk of hospitalization of respiratory syncytial virus (RSV)-infected infants before and during the palivizumab era. We present figures from the greater Stockholm area during the three seasons after the introduction of palivizumab and relate them to data based on 1400 hospitalizations for RSV disease in the same population area during 1987 through 1998. METHODS: The number of births, neonatal complications and palivizumab prescriptions was obtained. We retrieved information about all infant hospitalizations for confirmed RSV infections with risk factors and complications. Chronic lung disease (CLD) in preterm infants was defined as oxygen dependency beyond 36 weeks of postconceptional age. RESULTS: Eight hundred eighteen infants (1.3% of the population) were hospitalized for confirmed RSV infection. The hospitalization rates were 3.7% (24 of 642) among preterm infants with gestational age <33 weeks without CLD and 7.2% (14 of 195) in those with CLD. Palivizumab had been given to 235 infants, usually those with CLD and in need of continuous oxygen or steroid treatment or the <6 month-old infants with extremely preterm birth (gestational age <26 weeks). The risk of hospitalization for RSV disease was low, but this was the case also before the introduction of palivizumab. CONCLUSIONS: In countries with a low baseline risk of hospitalization for RSV infection, the benefit of palivizumab might not justify the cost of its widespread use. We advocate defining more rigorous prescription criteria.

Long-term impact of preterm birth on exercise capacity in healthy young men: a national population-based cohort study.

BACKGROUND: Increasing numbers of survivors of preterm birth are growing into adulthood today. Long-term health-effects of prematurity are still poorly understood, but include increased risk for diabetes, obesity and cardiovascular diseases in adult life. To test if reduced physical fitness may be a link in the causal chain of preterm birth and diseases in later life, the association of preterm birth and adult exercise capacity was investigated. The hypothesis was that preterm birth contributes independently of other risk factors to lower physical fitness in adulthood. METHODS AND FINDINGS: Population-based national cohort study of all males conscripting for military service in 1993-2001 and born in Sweden 1973-1983, n = 218,820. Data were retrieved from the Swedish Conscript Register, the Medical Birth Register and the Population and Housing Census 1990. Primary outcome was the results from maximal exercise test (Wmax in Watt) performed at conscription. Association to perinatal and socioeconomic risk factors, other co-variates and confounders were analysed. General linear modelling showed that preterm birth predicted low Wmax in a dose-response related pattern, with 25 Watt reduction in Wmax for the lowest gestational ages, those born ≤27 weeks. Low birth weight for gestational age also independently predicted low Wmax compared to normal and high birth weight (32 Watt reduction for those with a birth weight Standard Deviation Score <2). Low parental education was significantly associated with reduced Wmax (range 17 Watt), as well as both low and high current BMI, with severe obesity resulting in a 16 Watt deficit compared to Wmax top performance. CONCLUSION: Being born preterm as well as being born small for gestational age predicts low exercise capacity in otherwise healthy young men. The effect size of being born preterm equal or exceed that of other known risk factors for unfitness in adults, such as low parental education and overweight.