A secondary Outcome Analysis of a Randomized Trial Using a Mixed Lipid Emulsion Containing Fish Oil in Infants with Extremely Low Birth Weight: Cognitive and Behavioral Outcome at Preschool Age.

OBJECTIVE: To evaluate the impact of a parenteral lipid emulsion containing fish oil compared with a soybean oil based-lipid emulsion on the cognitive outcome and behavior of preschool children with extremely low birth weight. STUDY DESIGN: This was a retrospective secondary outcome analysis of a randomized controlled trial performed between June 2012 and June 2015. Infants with extremely low birth weight received either a mixed (soybean oil, medium chain triglycerides, olive oil, fish oil) or a soybean oil-based lipid emulsion for parenteral nutrition. Data from the Kaufman Assessment Battery for Children II, the Child Behavior Checklist 1.5-5, and anthropometry were collected from medical charts at 5.6 years of age. RESULTS: At discharge, 206 of the 230 study participants were eligible. At 5 years 6 months of age, data of 153 of 206 infants (74%) were available for analysis. There were no significant differences in Kaufman Assessment Battery for Children II scores for Sequential/Gsm, Simultaneous/Gv, Learning/Glr, and Mental Processing Index (mixed lipid: median, 97.5 [IQR, 23.5]; soybean oil: median, 96 [IQR, 19.5]; P = .43) or Child Behavior Checklist 1.5-5 scores for internalizing problems, externalizing problems, or total problems (mixed lipid: median, 37 [IQR, 12.3]; soybean oil: median, 37 [IQR, 13.5]; P = .54). CONCLUSIONS: A RandomForest machine learning regression analysis did not show an effect of type of lipid emulsion on cognitive and behavioral outcome. Parenteral nutrition using a mixed lipid emulsion containing fish oil did not affect neurodevelopment and had no impact on child behavior of infants with extremely low birth weights at preschool age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01585935.

A Randomized Trial of Parenteral Nutrition Using a Mixed Lipid Emulsion Containing Fish Oil in Infants of Extremely Low Birth Weight: Neurodevelopmental Outcome at 12 and 24 Months Corrected Age, A Secondary Outcome Analysis.

OBJECTIVE: To examine whether parenteral nutrition using a mixed lipid emulsion containing fish oil improves the neurodevelopmental outcomes of extremely low birth weight infants. STUDY DESIGN: The study is a secondary outcome analysis of a double-blind randomized trial of 230 extremely low birth weight infants performed at a single level IV neonatal care unit (Medical University Vienna; June 2012 to June 2015). Participants received either a mixed lipid emulsion composed of soybean oil, medium chain triglycerides, olive oil, and fish oil, or a soybean oil-based lipid emulsion for parenteral nutrition. Neurodevelopment of study participants was assessed at 12 and 24 months corrected age (August 2013 to October 2017) using the Bayley Scales of Infant-Toddler Development, third edition. RESULTS: At discharge, 206 of the 230 study participants were eligible. At 12 and 24 months corrected age, 174 of 206 (85%) and 164 of 206 (80%) infants were evaluated. At 12 months, there was no significant difference in cognitive (mixed lipid: median, 95 [IQR, 85-101]; soybean oil: median, 95 [IQR, 85-100]; P = .71), language (mixed lipid: median, 86 [IQR, 77-94], soybean oil: median, 89 [IQR, 79-94]; P = .48), or motor scores (mixed lipid: median, 88 [IQR, 76-94], soybean oil: median, 88 [IQR, 79-94]; P = .69). At 24 months, there was again no significant difference in cognitive (mixed lipid: median, 95 [IQR, 80-105], soybean oil: median, 95 [IQR, 90-105]; P = .17), language (mixed lipid: median, 89 [IQR, 75-97], soybean oil 89 [IQR, 77-100]; P = .54), and motor scores (mixed lipid: median, 94 [IQR, 82-103], soybean oil: median, 94 [IQR, 85-103]; P = .53). CONCLUSIONS: Parenteral nutrition using a mixed lipid emulsion containing fish oil did not improve neurodevelopment of extremely low birth weight infants at 12 and 24 months corrected age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01585935.

A Mixed Lipid Emulsion Containing Fish Oil and Its Effect on Electrophysiological Brain Maturation in Infants of Extremely Low Birth Weight: A Secondary Analysis of a Randomized Clinical Trial.

OBJECTIVE: To assess whether parenteral nutrition for infants of extremely low birth weight using a mixed lipid emulsion that contains fish oil influences electrophysiological brain maturation. STUDY DESIGN: The study is a prespecified secondary outcome analysis of a randomized controlled trial of 230 infants of extremely low birth weight receiving a mixed (soybean oil, medium-chain triglycerides, olive oil, and fish oil; intervention) or a soybean oil-based lipid emulsion (control). The study was conducted at a single-level IV neonatal care unit (Medical University Vienna; June 2012 to October 2015). Electrophysiological brain maturation (background activity, sleep-wake cycling, and brain maturational scores) was assessed biweekly by amplitude-integrated electroencephalography (birth to discharge). RESULTS: A total of 317 amplitude-integrated electroencephalography measurements (intervention: n = 165; control: n = 152) from 121 (intervention: n = 63; control: n = 58) of 230 infants of the core study were available for analysis. Demographic characteristics were not significantly different. By 28 weeks of postmenstrual age, infants receiving the intervention displayed significantly greater percentages of continuous background activity. Total maturational scores and individual scores for continuity, cycling, and bandwidth were significantly greater. Maximum maturational scores were reached 2 weeks earlier in the intervention group (36.4 weeks, 35.4-37.5) compared with the control group (38.4 weeks, 37.1-42.4) (median, IQR; P < .001). CONCLUSIONS: Using a mixed parenteral lipid emulsion that contains fish oil, we found that electrophysiological brain maturation was accelerated in infants who were preterm. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01585935.

A Mixed Lipid Emulsion for Prevention of Parenteral Nutrition Associated Cholestasis in Extremely Low Birth Weight Infants: A Randomized Clinical Trial.

OBJECTIVES: To examine whether a mixed lipid emulsion reduces the incidence of parenteral nutrition associated cholestasis (PNAC) in extremely low birth weight (ELBW, <1000 g) infants. STUDY DESIGN: This double-blind randomized trial of 230 ELBW infants (June 2012-October 2015) was performed at a single level IV neonatal intensive care unit. Patients received either a mixed lipid emulsion composed of soybean oil, medium chain triglycerides, olive oil, and fish oil-(intervention) or a soybean oil-based lipid emulsion (control) for parenteral nutrition. The primary outcome measure was PNAC (conjugated bilirubin >1.5 mg/dL [25 µmol/L] at 2 consecutive measurements). The study was powered to detect a reduction of PNAC from 25% to 10%. RESULTS: Reasons for noneligibility of 274 infants screened were refusal to participate (n = 16), death (n = 10), withdrawal of treatment (n = 5), higher order multiples (n = 9), and parents not available for consent (n = 4). Intention to treat analysis was carried out in 223 infants (7 infants excluded after randomization). Parenteral nutrition associated cholestasis was 11 of 110 (10.1%) in the intervention and 18 of 113 (15.9%) in the control group (P = .20). Multivariable analyses showed no statistically significant difference in the intention to treat (aOR 0.428, 95% CI 0.155-1.187; P = .10) or per protocol population (aOR 0.457, 95% CI 0.155-1.347; P = .16). There was no statistically significant effect on any other neonatal morbidity. CONCLUSIONS: The incidence of parenteral nutrition associated cholestasis was not significantly reduced using a mixed lipid emulsion in ELBW infants. TRIAL REGISTRATION: ClinicalTrials.govNCT01585935.

Starting enteral nutrition with preterm single donor milk instead of formula affects time to full enteral feeding in very low birthweight infants.

AIM: This study compared the impact of using either single donor breastmilk or formula to start enteral feeding in preterm infants, on the time to full enteral feeding, growth and morbidity. The milk was provided by other preterm mothers. METHODS: This was an observational prospective study, carried out from June 2012 to March 2013 at the Medical University of Vienna, Austria, on the effects of preterm single donor milk on 133 very low birthweight infants with a birthweight <1500 g and a gestational age <32 weeks until they were on full enteral feeding. They were compared to a retrospective group of 150 infants from March 2011 to May 2012 who received preterm formula. RESULTS: The time to full enteral feeding, defined as 140 mL/kg, was significantly shorter in the donor milk group than in the formula group (18 vs. 22 days, p = 0.01). Feeding donor milk was also associated with a lower incidence for retinopathy of prematurity (4% vs. 13%, p < 0.01) and culture-proven sepsis (11% vs. 23%, p < 0.01). CONCLUSION: Feeding preterm infants breastmilk from a single donor rather using formula was associated with a shorter time to full enteral feeding and lower incidences of retinopathy of prematurity and sepsis.

Human Milk Analyser shows that the lactation period affects protein levels in preterm breastmilk.

AIM: This study measured the composition of preterm human breastmilk, particularly the protein content, with the MIRIS Human Milk Analyser, compared our results with published values and determined the relationship between protein content and lactation period. METHODS: We analysed 83 samples of 24-hour pooled human milk from 76 mothers who delivered preterm infants weighing under 1500 g at less than 32 weeks of gestational age. The milk's protein, fat and energy were measured by the MIRIS Human Milk Analyser and compared to reference values. The relationship between protein content and lactation period was quantified. RESULTS: On average, the samples contained 1.1 ± 0.37 g (0.2-2.2 g) of protein, 3.2 ± 0.85 g (range 1.1-6.1 g) of fat, 6.6 ± 0.34 g of lactose (5.5-8.0 g) and 60 ± 11 kcal (39-94 kcal) of energy per 100 mL. The wide variations in macronutrient content were not influenced by the gestational age of the infant and the lactation day results from 70 of the mothers correlated inversely with the protein content (p < 0.0001; r = -0.42). The MIRIS proved useful, but some adjustments are needed. CONCLUSION: Variations in macronutrients were high in the breastmilk of women who delivered preterm babies and the protein content decreased with lactation. With adjustments, the MIRIS might provide a helpful tool for individualised fortification.

Probiotics (Lactobacillus acidophilus and Bifidobacterium infantis) prevent NEC in VLBW infants fed breast milk but not formula [corrected].

BACKGROUND: Specific probiotics prevent necrotizing enterocolitis (NEC). A mixture of lactobacilli and bifidobacteria (Infloran) was highly effective in Asian very-low-birth-weight (VLBW) infants. We analyzed the effect of Infloran on NEC, NEC severity, and the influence of enteral feedings (breast milk vs. formula) on NEC prevention in a cohort of European VLBW infants. METHODS: Infloran was implemented for routine use at our department. VLBW infants receiving probiotics were prospectively followed (2010-2012) and compared with historic controls (2008-2009). Data on NEC, neonatal morbidity, feeding tolerance, and descriptive parameters on NEC cases were analyzed. RESULTS: Infloran had no statistically significant impact on NEC (controls: 24/233 (10.3%); probiotics: 16/230 (7%); P = 0.2). However, NEC was significantly reduced in infants of the probiotics group who were fed any breast milk (20/179 (11.2%) vs. 10/183 (5.5%); P = 0.027), whereas it was ineffective in infants exclusively fed formula (4/54 (7.4%) vs. 6/44 (13.6%); P = 0.345). Occurrence of severe NEC (IIIb), time until full feeds, and gastric residuals were similar. CONCLUSION: Infloran was of lower efficacy in a European VLBW cohort and showed a reduction of NEC only in infants fed breast milk. Future studies should investigate the influence of feeding formula or breast milk on the effect of probiotics.

Homozygous SALL1 mutation causes a novel multiple congenital anomaly-mental retardation syndrome.

OBJECTIVE: To delineate a novel autosomal recessive multiple congenital anomaly-mental retardation (MCA-MR) syndrome in 2 female siblings of a consanguineous pedigree and to identify the disease-causing mutation. STUDY DESIGN: Both siblings were clinically characterized and homozygosity mapping and sequencing of candidate genes were applied. The contribution of nonsense-mediated messenger RNA (mRNA) decay to the expression of mutant mRNA in fibroblasts of a healthy carrier and a control was studied by pyrosequencing. RESULTS: We identified the first homozygous SALL1 mutation, c.3160C > T (p.R1054*), in 2 female siblings presenting with multiple congenital anomalies, central nervous system defects, cortical blindness, and absence of psychomotor development (ie, a novel recognizable, autosomal recessive MCA-MR). The mutant SALL1 transcript partially undergoes nonsense-mediated mRNA decay and is present at 43% of the normal transcript level in the fibroblasts of a healthy carrier. CONCLUSION: Previously heterozygous SALL1 mutations and deletions have been associated with dominantly inherited anal-renal-radial-ear developmental anomalies. We identified an allelic recessive SALL1-related MCA-MR. Our findings imply that quantity and quality of SALL1 transcript are important for SALL1 function and determine phenotype, and mode of inheritance, of allelic SALL1-related disorders. This novel MCA-MR emphasizes SALL1 function as critical for normal central nervous system development and warrants a detailed neurologic investigation in all individuals with SALL1 mutations.

Effect of fortifiers and additional protein on the osmolarity of human milk: is it still safe for the premature infant?

OBJECTIVES: The present guidelines of the American Academy of Pediatrics recommend that osmolarity not exceed 450 mOsm/kg (or approximately an osmolarity of 400 mOsm/L) for breast milk or infant formulae, to minimize the risk factors for necrotizing enterocolitis. A commercial protein supplement has been developed to meet special protein requirements (4.0-4.5 g · kg(-1) · day(-1)) of infants with a birth weight <1000 g. Because its effect on osmolarity has not been systematically studied, we characterized the effects of fortification on the osmolarity of human milk (HM). METHODS: Osmolarity of fresh and processed HM was measured at baseline, after fortification with a commercial HM fortifier and after further supplementation with additional protein increasing in 0.5-g steps up to 4.0 g. Measurements were performed immediately after adding fortifier and/or protein and after 24 hours. In addition, changes in osmolarity were determined after adding therapeutic additives such as iron, multivitamin supplement, and calcium-phosphorus capsules. RESULTS: Native HM samples (n = 84) had 297 mOsm/L, (median; 95% confidence interval 295-299 mOsm/L). Adding HM fortifier increased osmolarity up to 436 mOsm/L (95% confidence interval 431-441 mOsm/L). Additional protein supplementation increased osmolarity by 23.5 mOsm/L per 0.5-g step, up to a maximum of 605 mOsm/L. Pasteurization decreased osmolarity by 20-30 mOsm/L (P < 0.001), and storage for 24 hours slightly increased osmolarity (by 11.5 mOsm/L P = 0.0002). Therapeutic additives increased osmolarity up to 868 mOsm/L. CONCLUSIONS: Adding HM fortifier and additional protein to HM increased osmolarity to >400 mOsm/L and therefore above the recommended threshold. Because of the excessive increase in osmolarity combinations of HM + fortifier and additional protein should not be applied together with multivitamins or other additives.

Neurodevelopmental Outcome of Extremely Low Birth Weight Infants with Cholestasis at 12 and 24 Months.

INTRODUCTION: The aims of the study were to describe the neurodevelopmental outcome of extremely low birth weight (ELBW) infants with parenteral nutrition-associated cholestasis (PNAC) and to assess whether PNAC is associated with adverse neurodevelopmental outcome. METHODS: The study is a secondary analysis of controlled trial (June 2012-October 2017) on PNAC incidence in ELBW infants receiving two different parenteral lipid emulsions (mixed lipid emulsion containing fish oil vs. soybean oil-based). Neurodevelopmental follow-up at 12- and 24-month corrected age was compared in infants with and without PNAC. A machine learning-based regression analysis was used to assess whether PNAC was associated with adverse neurodevelopmental outcome. RESULTS: For assessment of neurodevelopmental outcome (Bayley-III), 174 infants were available at 12-month (PNAC: n = 21; no PNAC: n = 153) and 164 infants at 24-month (PNAC: n = 20; no PNAC: n = 144) corrected age. The neurodevelopment of ELBW infants with PNAC was globally delayed, with significantly lower cognitive, language, and motor scores at both 12- and 24-month corrected age. Regression analyses revealed that PNAC was associated with an adverse motor outcome. CONCLUSION: ELBW infants with PNAC are at increased risk for adverse neurodevelopmental outcome.

Extracellular vesicles from amniotic fluid, milk, saliva, and urine expose complexes of tissue factor and activated factor VII.

BACKGROUND: Tissue factor (TF) is expressed in the adventitia of the vessel wall and on extracellular vesicles (EVs) in body fluids. TF and activated coagulation factor (F) VII(a) together form the so-called extrinsic tenase complex, which initiates coagulation. AIM: We investigated whether EVs in amniotic fluid, milk, saliva, and urine expose functional extrinsic tenase complexes that can trigger coagulation. METHODS: Milk, saliva, and urine were collected from healthy breastfeeding women (n = 6), and amniotic fluid was collected from healthy women undergoing routine amniocentesis (n = 7). EVs were isolated from body fluids by size exclusion chromatography (SEC) and clotting experiments were performed in the presence and absence of antibodies against TF and FVIIa in normal plasma and in FVII-deficient plasma. The ability of body fluids to generate FXa also was determined. RESULTS: Amniotic fluid, milk, saliva, and urine triggered clotting of normal plasma and of FVII-deficient plasma, which was almost completely inhibited by an anti-FVII antibody and to a lesser extent by an anti-TF antibody. Fractionation of body fluids by SEC showed that only the fractions containing EVs triggered clotting in normal plasma and FVII-deficient plasma and generated FXa, which again was almost completely inhibited by an anti-FVII antibody and partially by an anti-TF antibody. CONCLUSION: Here we show that EVs from amniotic fluid, milk, saliva, and urine expose complexes of TF and FVIIa (i.e., extrinsic tenase complexes) that directly activate FX. Based on our present findings we propose that these EVs from normal body fluids provide hemostatic protection.

Packed red blood cell transfusion in preterm infants.

Premature infants commonly receive adult packed red blood cells (pRBCs) during their hospital stay. As adult erythrocytes differ substantially from those of preterm infants, transfusion of adult pRBCs into preterm infants can be considered inappropriate for the physiology of a preterm infant. An absence of standardisation of transfusion protocols makes it difficult to compare and interpret pertinent clinical data, as reflected by unclear associations between pRBC transfusion and complications related to prematurity, such as bronchopulmonary dysplasia, neurodevelopmental impairment, retinopathy of prematurity, or necrotising enterocolitis. The difficulty in interpreting clinical data is further increased by differences in study designs that either overestimate pRBC-associated complications of prematurity or have not yet been designed to directly link pRBC transfusions to their respective complications. Thus, neonatal transfusion practice has become an ongoing difficulty, in which differences in transfusion guidelines hinder the ability to generate comparable clinical data, and heterogeneity in clinical data prevents the implementation of standardised transfusion protocols. To overcome these issues, novel approaches with biochemical-clinical translational designs could enable clinicians to gather causal evidence instead of circumstantial correlation.

A Mixed-Lipid Emulsion Containing Fish Oil for the Parenteral Nutrition of Preterm Infants: No Impact on Visual Neuronal Conduction.

Fish oil is rich in omega-3 fatty acids and essential for neuronal myelination and maturation. The aim of this study was to investigate whether the use of a mixed-lipid emulsion composed of soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOF-LE) compared to a pure soybean oil-based lipid emulsion (S-LE) for parenteral nutrition had an impact on neuronal conduction in preterm infants. This study is a retrospective matched cohort study comparing preterm infants <1000 g who received SMOF-LE in comparison to S-LE for parenteral nutrition. Visual evoked potentials (VEPs) were assessed longitudinally from birth until discharge. The latencies of the evoked peaks N2 and P2 were analyzed. The analysis included 76 infants (SMOF-LE: n = 41 and S-LE: n = 35) with 344 VEP measurements (SMOF-LE: n= 191 and S-LE n = 153). Values of N2 and P2 were not significantly different between the SMOF-LE and S-LE groups. A possible better treatment effect in the SMOF-LE group was seen as a trend toward a shorter latency, indicating faster neural conduction at around term-equivalent age. Prospective trials and follow-up studies are necessary in order to evaluate the potential positive effect of SMOF-LE on neuronal conduction and visual pathway maturation.

The Ketogenic Diet Including Breast Milk for Treatment of Infants with Severe Childhood Epilepsy: Feasibility, Safety, and Effectiveness.

Objective: The ketogenic diet (KD) is a high-fat and restricted carbohydrate diet for treating severe childhood epilepsy. In infants, breast milk is usually fully replaced by a ketogenic formula. At our center, mothers are encouraged to include breastfeeding into the KD if still breastfeeding. This retrospective study describes achievement and maintenance of ketosis with or without inclusion of breast milk. Methods: Data were retrieved from a prospective longitudinal database of children treated with KD for epilepsy analyzing infants <1 year of age. The time to achieve clinically relevant ketosis (≥2 mmol/L beta-hydroxybutyrate) was compared with and without inclusion of breast milk into standard KD. Ketosis, nutritional intakes, effectiveness, adverse effects, and successful continuation of breastfeeding were evaluated. Results: A total of 79 infants were eligible for analysis. In 20% (16), breast milk was included. Infants with breast milk included into the KD achieved relevant ketosis in 47 hours (interquartile range [IQR] 24-95) compared with 41 hours (IQR 22-70; p = 0.779) in infants with standard KD. Beta-hydroxybutyrate at day 2 was 3.1 mmol/L (IQR 0.5-4.9) and 3.8 mmol/L (IQR 2.2-4.9). Infants with breast milk included received higher amounts of carbohydrates at baseline and calories at 3 months. Seizure freedom and adverse effects showed no relevant differences. No infections occurred in infants receiving breast milk. In two infants, KD was initiated with breast-feds after bottle-feeding KD formula. In 31%, breastfeeding was continued after the KD, and in 25%, inclusion of breast milk and breastfeeding was maintained until complete weaning. Before discharge from hospital, the amount of breast milk included was median 90 mL/day (IQR 53-203) equivalent to median 9% (IQR 6-15). Conclusions: Appropriate ketosis was achieved in most infants and maintained within 48 hours. Incorporation of breast milk into KD is feasible, safe, and effective.

Human milk triggers coagulation via tissue factor-exposing extracellular vesicles.

Almost a century ago, it was discovered that human milk activates the coagulation system, but the milk component that triggers coagulation had until now been unidentified. In the present study, we identify this component and demonstrate that extracellular vesicles (EVs) present in normal human milk expose coagulant tissue factor (TF). This coagulant activity withstands digestive conditions, mimicking those of breastfed infants, but is sensitive to pasteurization of pooled donor milk, which is routinely used in neonatal intensive care units. In contrast to human milk, bovine milk, the basis of most infant formulas, lacks coagulant activity. Currently, the physiological function of TF-exposing vesicles in human milk is unknown, but we speculate that these vesicles may be protective for infants. Another explanation could be nipple skin damage, which occurs in most breastfeeding women. Milk-derived TF-exposing EVs may seal the wound and thereby reduce bleeding and breast inflammation.

Mast cell-derived proteases control allergic inflammation through cleavage of IgE.

BACKGROUND: Cross-linking of mast cell-bound IgE releases proinflammatory mediators, cytokines, and proteolytic enzymes and is a key event in allergic inflammation. OBJECTIVE: We sought to study the effect of proteases released on effector cell activation on receptor-bound IgE and their possible role in the regulation of allergic inflammation. METHODS: Using molar ratios of purified recombinant tryptase and human IgE, we studied whether tryptase can cleave IgE. Similar experiments were performed with mast cell lysates in the presence or absence of protease inhibitors. IgE cleavage products were detected in supernatants of allergen cross-linked, cultivated mast cells and in tissue fluids collected from patients' skin after IgE-mediated degranulation. The effects of protamine, an inhibitor of heparin-dependent proteases on IgE-mediated allergic in vivo skin inflammation in human subjects were studied. RESULTS: We show that beta-tryptase, a major protease released during mast cell activation, cleaves IgE. IgE degradation products were detected in tryptase-containing tissue fluids collected from sites of allergic inflammation. The biologic significance of this mechanism is demonstrated by in vivo experiments showing that protease inhibition enhances allergic skin inflammation. CONCLUSION: We suggest that IgE cleavage by effector cell proteases is a natural mechanism for controlling allergic inflammation.

[Gestational diabetes mellitus (Update 2019)]. / Gestationsdiabetes (GDM) (Update 2019).

Gestational diabetes mellitus (GDM) is defined as a glucose tolerance disorder with onset during pregnancy and is associated with increased feto-maternal morbidity as well as long-term complications in mother and child. Women who fulfil the criteria of a manifest diabetes in early pregnancy (fasting plasma glucose >126 mg/dl, spontaneous glucose level >200 mg/dl or HbA1c > 6.5% before 20 weeks of gestation) should be classified as having manifest diabetes in pregnancy and treated as such. Screening for undiagnosed type 2 diabetes at the first prenatal visit (evidence level B) is particularly recommended in women at increased risk (history of GDM or prediabetes, malformation, stillbirth, successive abortions or birth weight >4500 g in previous pregnancies, obesity, metabolic syndrome, age >35 years, vascular disease, clinical symptoms of diabetes, e. g. glucosuria, or ethnic groups with increased risk for GDM/T2DM, e.g. Arabian countries, south and southeast Asia and Latin America). A GDM is diagnosed by an oral glucose tolerance test (OGTT) or a fasting glucose concentration ≥92 mg/dl. Performance of the OGTT (120 min, 75 g glucose) may already be indicated in the first trimester in high risk women but is mandatory between 24-28 gestational weeks in all pregnant women with previous non-pathological glucose metabolism (evidence level B). Based on the results of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study and following the recent WHO recommendations, GDM is present if the fasting plasma glucose level exceeds 92 mg/dl, the 1 h level exceeds 180 mg/dl or the 2 h level exceeds 153 mg/dl after glucose loading (OGTT international consensus criteria). A single increased value is sufficient for the diagnosis and a strict metabolic control is mandatory. After bariatric surgery an OGTT is not recommended due to the risk of postprandial hypoglycemia. All women with GDM should receive nutritional counselling, be instructed in self-monitoring of blood glucose and to increase physical activity to moderate intensity levels, if not contraindicated. If blood glucose levels cannot be maintained in the therapeutic range (fasting <95 mg/dl and 1 h postprandial <140 mg/dl) insulin therapy should be initiated as first choice. Maternal and fetal monitoring is required in order to minimize maternal and fetal/neonatal morbidity and perinatal mortality. After delivery all women with GDM have to be re-evaluated by a 75 g OGTT (WHO criteria) 4-12 weeks postpartum to reclassify the glucose tolerance and every 2 years in cases of normal glucose tolerance (evidence level B). All women have to be informed about their (sevenfold increased relative) risk of developing type 2 diabetes (T2DM) at follow-up and possible preventive measures, in particular weight management, healthy diet and maintenance/increase of physical activity. Monitoring of the development of children and recommendations for a healthy lifestyle are necessary for the whole family. Regular obstetric examinations including ultrasound examinations are recommended. Within the framework of neonatal care, neonates of GDM mothers should undergo blood glucose measurements and if necessary appropriate measures should be initiated.

Susceptibility to nasal and oral tolerance induction to the major birch pollen allergen Bet v 1 is not dependent on the presence of the microflora.

The indigenous microflora plays an integrative role in the maintenance of immunological homeostasis. Several studies reported that immunological tolerance is dependent on microbial colonization of the gut. In the present study, we investigated whether the absence of the microflora influences the sensitization process to an allergen as well as the ability to develop mucosal tolerance in a mouse model of birch pollen allergy. Germ-free or conventional BALB/c mice were intranasally or intragastrically pre-treated with the major birch pollen allergen Bet v 1 prior to sensitization with this allergen. Both germ-free and conventional mice displayed comparable Th2 biased immune responses after allergic sensitization. Oral as well as intranasal tolerization led to suppression of allergen-specific serum antibodies (IgG1, IgE, IgA) as well as cytokine production by splenocytes (IL-5, IFN-gamma) in both germ-free and conventional animals. Peyer's patches of germ-free animals were approximately 20 times smaller than in conventional animals, but the relative distribution of lymphocyte subpopulations was equal. We conclude that the absence of the microflora does not influence the ability to mount Th2 responses nor to establish tolerance towards the aeroallergen Bet v 1. Our findings may challenge the view that the commensal microflora is a key factor for breakdown of physiological tolerance and allergy development.

Can Sequential Coagulation Monitoring Predict Major Haemorrhage in Extremely Low Birth Weight Infants?

INTRODUCTION: Bleeds such as intra-ventricular (IVH) and pulmonary haemorrhage (PH) are life-threatening events in extremely low birth weight (ELBW) infants. Serial coagulation monitoring by measuring the international normalized ratio (INR) with small volume samples might facilitate early diagnosis and possibly prevent major bleeds. MATERIALS AND METHODS: This was a prospective longitudinal study performed in ELBW infants, who received serial INR monitoring by point of care testing during their first 30 days of life. The primary objective was to explore whether INR monitoring could predict major bleeding events (IVH, PH). Secondary objectives were mortality and feasibility in this patient population. RESULTS: A total of 127 ELBW infants were stratified into a bleeding and a non-bleeding group. Bleeding events occurred in 31% (39/127) of the infants, whereupon 24% developed IVH and 9% PH. Infants in the bleeding group were 4 days younger at birth (p = 0.05) and had a substantially higher mortality rate of 26% versus 5% in controls (p = 0.005). Median INR during the first 3 days before a bleeding event was 1.55 (95% confidence interval [CI]: 1.39-1.74) compared with the control group with 1.45 (95% CI: 1.44-1.58; p = 0.81). Platelet counts were significantly lower in the bleeding group on the 3rd day and during the 2nd to 4th week of life. DISCUSSION: Serial coagulation monitoring by an INR point of care testing is feasible in ELBW infants but could not predict bleeding events. Further studies with daily monitoring of INR and platelet counts during the first days of life might be able to more precisely detect a risk of major haemorrhage in ELBW infants.