Longitudinal changes in bifidobacterial population during the first two years of life.

Early life microbiota encompasses of a large percentage of Bifidobacterium, while it is not sufficiently understood how the Bifidobacterium population develops after infant's birth. Current study investigated the longitudinal changes in Bifidobacterium population during the first two years of life in 196 term born infants (1,654 samples) using 16S rRNA-23S rRNA internal transcribed spacer (ITS) sequence analysis. Throughout the first two years of life, Bifidobacterium breve, Bifidobacterium longum subsp. longum and Bifidobacterium adolescentis were most dominant and prevalent in the Bifidobacterium population, while B. breve had the highest relative abundance and prevalence during the first week of life and it was taken over by B. longum subsp. longum around two years after birth. Sampling time points, early antibiotic(s) exposure (effect only measurable within a month after birth), delivery mode (effect still detectable two-months after birth) and feeding mode (effect lasted until six months after birth), significantly contributed to the overall variation in the bifidobacterial population. From six months onwards, introducing of solid food and cessation of breastfeeding were accompanied with drastic changes in the composition in bifidobacterial population. Altogether, current study confirmed the effect of potential contributors to the longitudinal changes within the bifidobacterial population during the first two years of life. Registered at https://clinicaltrials.gov: NCT02536560.

The influence of very preterm birth on adolescent EEG connectivity, network organization and long-term outcome.

OBJECTIVE: The aim of this study was to explore differences in functional connectivity and network organization between very preterm born adolescents and term born controls and to investigate if these differences might explain the relation between preterm birth and adverse long-term outcome. METHODS: Forty-seven very preterm born adolescents (53% males) and 54 controls (54% males) with matching age, sex and parental educational levels underwent high-density electroencephalography (EEG) at 13 years of age. Long-term outcome was assessed by Intelligence Quotient (IQ), motor, attentional functioning and academic performance. Two minutes of EEG data were analysed within delta, theta, lower alpha, upper alpha and beta frequency bands. Within each frequency band, connectivity was assessed using the Phase Lag Index (PLI) and Amplitude Envelope Correlation, corrected for volume conduction (AEC-c). Brain networks were constructed using the minimum spanning tree method. RESULTS: Very preterm born adolescents had stronger beta PLI connectivity and less differentiated network organization. Beta AEC-c and differentiation of AEC-c based networks were negatively associated with long-term outcomes. EEG measures did not mediate the relation between preterm birth and outcomes. CONCLUSIONS: This study shows that very preterm born adolescents may have altered functional connectivity and brain network organization in the beta frequency band. Alterations in measures of functional connectivity and network topologies, especially its differentiating characteristics, were associated with neurodevelopmental functioning. SIGNIFICANCE: The findings indicate that EEG connectivity and network analysis is a promising tool for investigating underlying mechanisms of impaired functioning.

The effect of enteral supplementation of specific neutral and acidic oligosaccharides on the faecal microbiota and intestinal microenvironment in preterm infants.

We aimed to determine the effects of enteral supplementation of a prebiotic mixture of neutral and acidic oligosaccharides (scGOS/lcFOS/pAOS) on the faecal microbiota and microenvironment in preterm infants. Furthermore, we determined the influence of perinatal factors on the development of the faecal microbiota. In a randomised controlled trial, preterm infants with gestational age <32 weeks and/or birth weight <1,500 g received enteral supplementation of scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Faecal microbiota, as measured with fluorescent in situ hybridisation (FISH), and microenvironment [short-chain fatty acids (SCFAs), pH, sIgA] were measured at four time points: before the start of the study and at days 7, 14 and 30 of life. In total, 113 preterm infants were included. Enteral supplementation of the prebiotic mixture increased the total bacteria count at day 14 (Exp 3.92; 95 % confidence interval [CI] 1.18-13.04, p = 0.03), but not at day 30 (Exp 1.73; 95 % CI 0.60-5.03, p = 0.31). There was a trend toward increased bifidobacteria counts. There was a delayed intestinal colonisation of all bacteria. Enteral supplementation of the prebiotic mixture decreased the faecal pH (Exp 0.71; 95 % CI 0.54-0.93, p = 0.01) and there was a trend toward increased acetic acid compared to the placebo group (Exp 1.09; 95 % CI 0.99-1.20, p = 0.10). There was no effect on sIgA (Exp 1.94; 95 % CI 0.28-13.27, p = 0.50). Antibiotics decreased the total bacteria count (Exp 0.13; 95 % CI 0.08-0.22, p < 0.001). Enteral supplementation of a prebiotic mixture of neutral and acidic oligosaccharides increases the postnatal intestinal colonisation. However, the extensive use of broad-spectrum antibiotics in preterm infants decreased the growth of all intestinal microbiota, thereby, delaying the normal microbiota development.

The effect of neutral and acidic oligosaccharides on stool viscosity, stool frequency and stool pH in preterm infants.

AIM: To determine the effect of neutral oligosaccharides [small-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS)] in combination with acidic oligosaccharides (pAOS) on stool viscosity, stool frequency and stool pH in preterm infants. METHODS: In this explorative RCT, preterm infants with gestational age <32 weeks and/or birth weight <1500 g received enteral supplementation with scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Stool samples were collected at day 30 after birth. RESULTS: In total, 113 infants were included. Baseline and nutritional characteristics were not different between both groups. Stool viscosity at day 30 was lower in the prebiotics group (16.8N) (3.9-67.8) compared with the placebo group (26.3N) (1.3-148.0) (p = 0.03; 95% CI -0.80 to 0.03). There was a trend towards higher stool frequency in the prebiotics group (3.1 ± 0.8) compared with the placebo group (2.8 ± 0.7) (p = 0.15; 95% CI -0.08 to 0.52). Stool pH at day 30 was lower in the in the prebiotics group (5.9 ± 0.6) compared with the placebo group (6.2 ± 0.3) (p = 0.009; 95% CI 0.08 to 0.53). CONCLUSIONS: Enteral supplementation of a prebiotic mixture consisting of neutral (scGOS/lcFOS) and acidic oligosaccharides (pAOS) decreases stool viscosity and stool pH with a trend towards increased stool frequency in preterm infants. The inclusion of pAOS in a formula containing a mixture of scGOS/lcFOS does not add specific advantages to the formula in terms of stool viscosity, frequency, pH as well as feeding tolerance.

Transplacental transport of IgG antibodies to preterm infants: a review of the literature.

Newborn infants, especially preterm infants, have an immature immune system, which is not capable to actively protect against vaccine-preventable infections. Therefore, the newborn is dependent on transplacental transport of Immunoglobulin G (IgG), an active, FcRn receptor mediated process. Fetal IgG rises from approximately 10% of the maternal concentration at 17-22weeks of gestation to 50% at 28-32weeks of gestation. If transplacental acquired IgG is lower in preterm than in term infants, preterm infants are especially at risk for these vaccine-preventable diseases. The aim of this study was to review the transplacental transfer of IgG against vaccine-preventable diseases (measles, rubella, varicella-zoster, mumps, Haemophilus influenza type B, diphtheria, tetanus, pertussis and polio) to (pre)term infants and to identify factors that influence the transplacental transfer of these antigens. After selection, 18 studies on transplacental transport to preterm infants were included. In general, these studies showed for all antibodies that preterm infants have lower antibody concentrations compared with term infants. Maternal and infants antibody concentrations showed a strong correlation in 7 of the included studies. Infant antibody concentration was not associated with parity, maternal age, height or weight. Infants of vaccinated mothers had lower anti-measles antibody titers than infants of natural immunized mothers. IgG titers of preterm infants decrease earlier in life below protective antibody titers than term infants. Combined with their immature immune system, this puts preterm infants at increased risk for vaccine-preventable diseases.

Intestinal microbiota in allergic and nonallergic 1-year-old very low birth weight infants after neonatal glutamine supplementation.

AIM: Previously, glutamine-enriched enteral nutrition in very low birth weight infants (VLBW) decreased the incidence of atopic dermatitis at age 1 year. The aim of this study was to determine whether this effect is related to changes in intestinal bacterial species that are associated with allergy, such as bifidobacteria, clostridium histolyticum, clostridium lituseburense (Chis/lit group) and Escherichia coli at age 1 year. METHODS: Eighty-nine infants were eligible for this follow-up study, conducted at a Tertiary care hospital. Bifidobacteria, Chis/lit group and E. coli were measured by fluorescent in situ hybridization in faecal samples collected at age 1 year. Information on allergic and infectious diseases was previously determined by questionnaire. RESULTS: Seventy-two of 89 (81%) infants were participated. Prevalence of all studied species was not different between glutamine-supplemented and control groups. Allergic infants were less frequently colonized with bifidobacteria than nonallergic infants (p =0.04). Between neonatal period and 1 year, prevalence of bifidobacteria was increased (p < 0.001), of Chis/lit group was unchanged (p=0.84), and of E. coli was decreased (p < 0.001). CONCLUSION: The beneficial effect of glutamine-enriched enteral nutrition on the incidence of atopic dermatitis in the first year of life in VLBW infants is not related to changes in bifidobacteria, Chis/lit group or E. coli. Allergic VLBW infants are less frequently colonized with bifidobacteria compared to nonallergic VLBW infants.

Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development.

We describe the effect on the neonate of administration of rituximab to a woman with idiopathic thrombocytopenic purpura (ITP). Rituximab, an anti-CD20 antibody, was given weekly for 4 weeks to a woman with ITP in her third trimester of pregnancy. One month after the last rituximab administration a healthy girl was born. She had normal growth and development during the first six months. At birth, B-lymphocytes were not detectable. Rituximab levels in mother and neonate were 24000 and 6700 ng/mL, respectively. Only 7 cases of rituximab administration during pregnancy were described. No adverse events are described for fetus and neonate. We demonstrate that rituximab passes the placenta and inhibits neonatal B-lymphocyte development. However, after 6 months B-lymphocyte levels normalized and vaccination titres after 10 months were adequate. No infection-related complications occurred. Rituximab administration during pregnancy appears to be safe for the child but further studies are warranted.

[Post-mortem MRI in newborns when autopsy is not permitted]. / MRI post mortem bij pasgeborenen bij wie obductie niet wordt toegestaan.

2 newborns, boys weighing 1400 and 950 g, died 2 and 8 hours after birth respectively. Autopsy was not permitted but MRI was possible. In the first newborn, characteristic abnormalities ofa Potter's sequence were found: pulmonary hypoplasia, missing kidneys and ureters and a rudimentary bladder. Clinically, a small chest, low-positioned ears, a flattened nose, a retracted chin, contractures of both knees and a talipes equinus of both feet had already been observed. In the second newborn, an MRI scan of the skull revealed a torn cerebellar tentorium with intracranial bleeding. The cause of death in newborns is often unknown. Autopsy is the gold standard for determining the cause of death. However for a variety of reasons, many parents do not give informed consent for autopsy. In such cases, post-mortem MRI may be an alternative. Abnormalities ofthe central nervous system, muscles and internal organs can usually be clearly visualized using MRI. However, the diagnosis of cardiac abnormalities using this technique is more difficult.

An unusual hotspot in a young woman with Hodgkin's lymphoma.

A young woman has started cancer treatment because of a Hodgkin's lymphoma. After four months of chemotherapy, a PET scan showed an unexplained hotspot in the right lower abdomen. This was later explained by an unsuspected pregnancy. Our case emphasizes the importance of a pregnancy test in all women in the reproductive age before starting cancer treatment.

Mannose-binding lectin (MBL) genotype in relation to risk of nosocomial infection in pre-term neonates in the neonatal intensive care unit.

Mannose-binding lectin (MBL) plays an important role in the innate immune response. Three alleles in the MBL gene, and one allele of the promoter, independently cause low serum MBL levels as compared with the wild-type. This study investigated the relationship between MBL genotype and the occurrence of nosocomial infection among neonates in a neonatal intensive care unit (NICU). Prospectively gathered information concerning nosocomial infection was available for 742 neonates from a recently performed surveillance study in an NICU. DNA was isolated from Guthriecards for a subgroup of 204 neonates who stayed in the NICU for > or =4 days. After a pre-PCR for the MBL gene in blood spots on Guthriecards, mutations were analysed by real-time PCR to detect six mutations in the MBL gene. An MBL genotype could be determined for 186 neonates. As compared to term neonates, genotypes encoding MBL-deficient haplotypes were significantly more prevalent among pre-term neonates. Forty-one of these neonates developed sepsis, with blood cultures yielding coagulase-negative staphylococci in 25 cases. Pneumonia occurred in 30 cases, with various causative organisms. No relationship was found between MBL genotype and the risk of nosocomial sepsis or pneumonia, even after correction for birth-weight, perhaps because of an insufficient correlation between genotype and the concentration of functional MBL. In addition, most bloodstream infections in the NICU were caused by coagulase-negative staphylococci, to which MBL binds poorly.

Nosocomial infections in a Dutch neonatal intensive care unit: surveillance study with definitions for infection specifically adapted for neonates.

The incidence of nosocomial infection in neonatal intensive care units (NICUs) is high compared with other wards. However, no definitions for hospital-acquired infection are available for NICUs. The aim of this study was to measure the incidence of such infections and to identify risk factors in the NICU of the VU University Medical Center, which serves as a level III regional NICU. For this purpose, a prospective surveillance was performed in 1998-2000. We designed definitions by adjusting the current definitions of the Centers for Disease Control and Prevention (CDC) for children <1 year of age. Birth weight was stratified into four categories and other baseline risk factors were dichotomized. Analysis of risk factors was performed by Cox regression with time-dependent variables. The relationship between the Clinical Risk Index for Babies (CRIB) and nosocomial infection was investigated. Furthermore, for a random sample of cases, we determined whether bloodstream infection and pneumonia would also have been identified with the CDC definitions. Seven hundred and forty-two neonates were included in the study. One hundred and ninety-one neonates developed 264 infections. Bloodstream infection (N=138, 14.9/1000 patient-days) and pneumonia (N=69, 7.5/1000 patient-days) were the most common infections. Of bloodstream infections, 59% were caused by coagulase-negative staphylococci; in 21% of neonates, blood cultures remained negative. In 25% of pneumonias, Enterobacteriaceae were the causative micro-organisms; 26% of cultures remained negative. Compared with the Nosocomial Infections Surveillance System (NNIS) of the CDC, our device utilization ratios and device-associated nosocomial infection rates were high. The main risk factors for bloodstream infection were birth weight [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.45-2.17] and parenteral feeding with hospital-pharmacy-produced, all-in-one mixture 'Minimix' (HR 3.69, 95%CI 2.03-6.69); administration of intravenous antibiotics (HR 0.39, 95%CI 0.26-0.56) was a protective risk factor. The main risk factors for pneumonia were low birth weight (HR 1.37, 95%CI 1.01-1.85) and mechanical ventilation (HR 9.69, 95%CI 4.60-20.4); intravenous antibiotics were protective (HR 0.37, 95%CI 0.21-0.64). In a subcohort of 232 very-low-birthweight neonates, the CRIB was not predictive for infection. With the CDC criteria, only 75% (21/28) of bloodstream infections and 87.5% of pneumonias (21/24) would have been identified. In conclusion, our local nosocomial infection rates are high compared with those of NICUs participating in the NNIS. This can be partially explained by: (1) the use of our definitions for nosocomial infection, which are more suitable for this patient category; and (2) the high device utilization ratios.

[Fever, coughing and/or wheezing in young children: consider the possibility of foreign body aspiration]. / Koorts, hoesten en/of piepen bij jonge kinderen: vergeet het corpus alienum niet.

Three children, 2 girls aged 1.5 and 3 years and a 2-year-old boy, experienced coughing, wheezing and/or fever for several days or weeks. The first girl was treated for asthma, the other two children for pneumonia. Because the symptoms persisted in all three children after treatment was started, the diagnosis of foreign body aspiration was suggested and confirmed by bronchoscopy. The foreign body was removed during the bronchoscopy and in the boy, a mucosal lesion in the piriform fossa was sutured. Thereafter, all the children recovered completely. In children with persistent coughing, wheezing or fever despite treatment for pneumonia or asthma and in absence of a characteristic acute incident, foreign body aspiration should be considered.

Minimal enteral feeding, fetal blood flow pulsatility, and postnatal intestinal permeability in preterm infants with intrauterine growth retardation.

OBJECTIVE: To study the effect of minimal enteral feeding (MEF) on intestinal permeability and feeding tolerance in preterm infants with intrauterine growth retardation (gestational age < 37 weeks, birth weight for gestational age p < 10). Furthermore, to determine whether fetal blood flow pulsatility or intestinal permeability predict feeding tolerance in these infants. DESIGN: Randomised controlled trial. METHODS: Within 48 hours of birth, infants were randomised to MEF or no enteral feeding (NEF) for five days in addition to parenteral feeding. Intestinal permeability was measured by the sugar absorption test before (SAT1) and after (SAT2) the study. The sugar absorption test measured the urinary lactulose/mannitol (LM) ratio after oral ingestion of a solution (375 mosm) containing mannitol and lactulose. Charts of all infants were assessed for measures of feeding tolerance. Fetal blood flow pulsatility index (U/C ratio) was measured within the seven days before birth. RESULTS: Of the 56 infants enrolled, 42 completed the study: 20 received MEF and 22 NEF. The decrease in LM ratio (LM ratio 1 - LM ratio 2) was not significantly different between the two groups (0.25 v 0.11; p = 0.14). Feeding tolerance, growth, and incidence of necrotising enterocolitis were not significantly different between the two groups. Neither the U/C nor the LM ratio 1 predicted feeding tolerance. CONCLUSIONS: The results suggest that MEF of preterm infants with intrauterine growth retardation has no effect on the decrease in intestinal permeability after birth. Neither fetal blood flow pulsatility nor intestinal permeability predicts feeding tolerance.

[Diagnostic image (182). A neonate with a bend in one lower leg. Posteromedial bowing of tibia and fibula]. / Diagnose in beeld (182). Een zuigeling met een knik in het onderbeen. Posterior bowing van tibia en fibula.

A preterm girl was born with posteromedial bowing of the left lower leg, and dorsiflexion and calcaneovalgus position of the left foot. The bend reduced spontaneously.

Intestinal permeability in relation to birth weight and gestational and postnatal age.

OBJECTIVE: To determine the relation between intestinal permeability and birth weight, gestational age, postnatal age, and perinatal risk factors in neonates. STUDY DESIGN: Intestinal permeability was measured by the sugar absorption test within two days of birth and three to six days later in preterm and healthy term infants. In the sugar absorption test, the urinary lactulose/mannitol ratio is measured after oral ingestion of a solution (375 mosm) of lactulose and mannitol. RESULTS: A first sugar absorption test was performed in 116 preterm (26-36 weeks gestation) and 16 term infants. A second test was performed in 102 preterm and nine term infants. In the preterm infants, the lactulose/mannitol ratio was not related to gestational age (r = -0.09, p = 0.32) or birth weight (r = 0.07, p = 0.43). The median lactulose/mannitol ratio was higher if measured less than two days after birth than when measured three to six days later (0.427 and 0.182 respectively, p<0.001). The lactulose/mannitol ratio was higher in preterm infants than term infants if measured within the first 2 days of life (0.404 and 0.170 respectively, p < 0.001), but not different three to six days later (0.182 and 0.123 respectively, p = 0.08). In multiple regression analysis of perinatal risk factors, only umbilical arterial pH correlated with the lactulose/mannitol ratio in preterm infants less than 2 days of age (T = -1.98, p = 0.05). CONCLUSIONS: In preterm infants (26-36 weeks gestation), intestinal permeability is not related to gestational age or birth weight but is higher during the first 2 days of life than three to six days later. It is higher in preterm infants than in healthy term infants only if measured within two days of birth. This suggests rapid postnatal adaptation of the small intestine in preterm infants.