Symptom Burden and Factors Associated with Acute Respiratory Infections in the First Two Years of Life-Results from the LoewenKIDS Cohort.

Acute respiratory infections (ARIs) are the most common childhood illnesses worldwide whereby the reported frequency varies widely, often depending on type of assessment. Symptom diaries are a powerful tool to counteract possible under-reporting, particularly of milder infections, and thus offer the possibility to assess the full burden of ARIs. The following analyses are based on symptom diaries from participants of the German birth cohort study LoewenKIDS. Primary analyses included frequencies of ARIs and specific symptoms. Factors, which might be associated with an increased number of ARIs, were identified using the Poisson regression. A subsample of two hundred eighty-eight participants were included. On average, 13.7 ARIs (SD: 5.2 median: 14.0 IQR: 10-17) were reported in the first two years of life with an average duration of 11 days per episode (SD: 5.8, median: 9.7, IQR: 7-14). The median age for the first ARI episode was 91 days (IQR: 57-128, mean: 107, SD: 84.5). Childcare attendance and having siblings were associated with an increased frequency of ARIs, while exclusive breastfeeding for the first three months was associated with less ARIs, compared to exclusive breastfeeding for a longer period. This study provides detailed insight into the symptom burden of ARIs in German infants.

Anatomic accuracy, physiologic characteristics, and fidelity of very low birth weight infant airway simulators.

BACKGROUND: Medical simulation training requires realistic simulators with high fidelity. This prospective multi-center study investigated anatomic precision, physiologic characteristics, and fidelity of four commercially available very low birth weight infant simulators. METHODS: We measured airway angles and distances in the simulators Premature AirwayPaul (SIMCharacters), Premature Anne (Laerdal Medical), Premie HAL S2209 (Gaumard), and Preterm Baby (Lifecast Body Simulation) using computer tomography and compared these to human cadavers of premature stillbirths. The simulators' physiologic characteristics were tested, and highly experienced experts rated their physical and functional fidelity. RESULTS: The airway angles corresponded to those of the reference cadavers in three simulators. The nasal inlet to glottis distance and the mouth aperture to glottis distance were only accurate in one simulator. All simulators had airway resistances up to 20 times higher and compliances up to 19 times lower than published reference values. Fifty-six highly experienced experts gave three simulators (Premature AirwayPaul: 5.1 ± 1.0, Premature Anne 4.9 ± 1.1, Preterm Baby 5.0 ± 1.0) good overall ratings and one simulator (Premie HAL S2209: 2.8 ± 1.0) an unfavorable rating. CONCLUSION: The simulator physiology deviated significantly from preterm infants' reference values concerning resistance and compliance, potentially promoting a wrong ventilation technique. IMPACT: Very low birth weight infant simulators showed physiological properties far deviating from corresponding patient reference values. Only ventilation with very high peak pressure achieved tidal volumes in the simulators, as aimed at in very low birth weight infants, potentially promoting a wrong ventilation technique. Compared to very low birth weight infant cadavers, most tested simulators accurately reproduced the anatomic angular relationships, but their airway dimensions were relatively too large for the represented body. The more professional experience the experts had, the lower they rated the very low birth weight infant simulators.

Short courses of dual-strain probiotics appear to be effective in reducing necrotising enterocolitis.

AIM: Prophylactic probiotics to reduce necrotising enterocolitis (NEC) are mostly given for at least 28 days or until discharge. We describe the effects of a shorter duration dosing strategy. METHODS: Retrospective cohort study of neonates (birthweight 400-1500 g) in three neonatal intensive care units in Switzerland and Germany that embarked on probiotic prophylaxis given for 10 or 14 days, employing a fixed combination (Lactobacillus acidophilus plus Bifidobacterium infantis, each 10(9) CFU/day) licensed as a drug in Switzerland. Probiotics were initiated upon discontinuation of antibiotics, or on day 1-3 in infants without antibiotics. Repeat probiotic courses were given whenever antibiotics had been instituted and were discontinued. RESULTS: Birthweight and gestational age were similar in the two 24-month pre- and postimplementation cohorts. NEC rates fell from 33 of 633 (5.2%) to 8 of 591 infants alive at three days (1.4%; risk ratio (RR) 0.26, 95% confidence interval (CI) 0.12-0.55). The drop in NEC was significant both for infants of 400-999 g (6.4% to 2.5%) and 1000-1500 g birthweight (4.4% to 0.6%). Mortality was 5.1% (32/633) without, as opposed to 3.5% (21/591) with probiotics, respectively (RR 0.69, 95% CI 0.41-1.19). CONCLUSION: Short courses of a dual-strain probiotics appear to be effective in reducing NEC.

Prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics and outcome in very low birth weight infants.

OBJECTIVE: To evaluate outcome data in an observational cohort of very low birth weight infants of the German Neonatal Network stratified to prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics. STUDY DESIGN: Within the observational period (September 1, 2010, until December 31, 2012, n=5351 infants) study centers were categorized into 3 groups based on their choice of Lactobacillus acidophilus/Bifidobacterium infantis use: (1) no prophylactic use (12 centers); (2 a/b) change of strategy nonuser to user during observational period (13 centers); and (3) use before start of observation (21 centers). Primary outcome data of all eligible infants were determined according to center-specific strategy. RESULTS: The use of probiotics was associated with a reduced risk for necrotizing enterocolitis surgery (group 1 vs group 3: 4.2 vs 2.6%, P=.028; change of strategy: 6.2 vs 4.0%, P<.001), any abdominal surgery, and hospital mortality. Infants treated with probiotics had improved weight gain/day, and probiotics had no effect on the risk of blood-culture confirmed sepsis. In a multivariable logistic regression analysis, probiotics were protective for necrotizing enterocolitis surgery (OR 0.58, 95% CI 0.37-0.91; P=.017), any abdominal surgery (OR 0.7, 95% CI 0.51-0.95; P=.02), and the combined outcome abdominal surgery and/or death (OR 0.43; 95% CI 0.33-0.56; P<.001). CONCLUSIONS: Our observational data support the use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics to reduce the risk for gastrointestinal morbidity but not sepsis in very low birth weight infants.

Developmental delay in hypoxia-induced HO-1 expression predisposes to gut injury.

AIMS: Necrotizing enterocolitis (NEC) is an often fatal disease that affects 5-8% of preterm newborn infants but does not occur in older infants and children. As carbon monoxide (CO) may exert protective effects against NEC, we assessed patterns of intestinal injury and investigated the expression of the CO-producing enzyme heme oxygenase-1 (HO-1) in mature and immature rat guts in response to hypercapnia and reoxygenation (H/R). METHODS: Gut barrier failure (increased permeability for dextran) was assessed in immature (newborn rats) and mature rats (weanling rats) subjected to H/R. Their guts were assayed for apoptosis (caspase-3 activity), expression of inducible NO synthase (iNOS) and HO-1 [quantitative polymerase chain reaction (PCR) and immunoblot]. The role of HO-1 was investigated in experiments involving HO-1 induction by hemin or HO-1 inhibition by tin protoporphyrin IX. RESULTS: In the mature gut, H/R induced the expression of intestinal HO-1 within 48 h, whereas in the immature gut HO-1 up-regulation was delayed by 48 h. Immature, but not mature, rats exhibited gut barrier failure, apoptosis and increased iNOS expression upon H/R. After the induction of HO-1 by hemin, gut barrier failure and apoptosis were abrogated in the immature gut, while the inhibition of HO-1 by tin protoporphyrin IX significantly aggravated gut injury. CONCLUSIONS: These experiments point to an immaturity-dependent lag in HO-1 expression upon H/R in the immature gut and link low HO-1 to gut barrier failure induced by H/R in a non-infectious dam-fed animal model of gut injury.

Somatic classification of neonates based on birth weight, length, and head circumference: quantification of the effects of maternal BMI and smoking.

We defined neonates as small, appropriate, or large for gestational age (SGA, AGA, LGA) based on birth weight, length, and head circumference. We analyzed the effects on the somatic classification of maternal body mass index (BMI) (<18.5, 18.5-24.99, 25.0-29.99, ≥ 30) and smoking during pregnancy (0, 1-7, 8-14, ≥ 15 cigarettes daily). Data were from the German Perinatal Survey (1998-2000; 433,669 cases). The following refers to the classification by birth weight. In the normal maternal weight population SGA rates increased with cigarette consumption: 9.8%, 17.8%, 21.6%, and 25.4% for non-smokers, and smokers of 1-7, 8-14, and ≥ 15 cigarettes daily, respectively. In non-smoking underweight women the SGA rate was 17.4%. In underweight smokers of ≥ 15 cigarettes daily the SGA rate was 38.5% [odds ratio 5.77, 95% confidence interval 5.10-6.53, compared with normal weight non-smokers]. In the normal maternal weight population, LGA rates were 9.9%, 5.3%, 4.6%, and 3.5% for non-smokers, and smokers of 1-7, 8-14, and ≥ 15 cigarettes daily, respectively. In the obese, LGA rates were 20.9% (non-smokers) and 11.4% (≥ 15 cigarettes). Similar findings were obtained for the somatic classifications based on birth length and head circumference. Results for the various combinations of maternal BMI and smoking status in the three classification systems are described. Our findings may assist in individualized risk assessment for SGA and LGA births.

Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy.

UNLABELLED: HYPOTHESIS/ INTRODUCTION: : We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism. MATERIAL AND METHODS: : One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charité obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done. RESULTS: : Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 ± 0.70% vs. 6.21 ± 0.66% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 ± 0.80%) compared to II mothers delivering boys (6.21 ± 0.81%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension. CONCLUSIONS: : Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex.

Maternal and fetal PROGINS progesterone receptor polymorphism reduces the risk for transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn (TTN) is the most common perinatal respiratory disorder. It was suggested that the pathogenesis of TTN might involve altered activity of female sex hormones. This study analyzed whether the PROGINS progesterone receptor polymorphism, which is less responsive to progesterone, is associated with TTN. METHODS: A cohort of 2352 infants born to Caucasian women at the Obstetrics Department of the Charite was investigated prospectively. The collected information included the occurrence of respiratory disorders, birth weight, gestational age at delivery, mode of delivery, and maternal morbidity. Mothers and newborns were genotyped for the PROGINS progesterone receptor polymorphism. Statistical analyses considered correction for confounding factors. RESULTS: The presence of the mutated T2-allele either in mothers or in infants was associated with a reduction of the incidence of TTN in a gene dose-dependent manner (mothers T1/T1: 6.6%, T1/T2: 4.3% T2/T2: 2.3%, p < 0.01; infants T1/T1: 6.5%, T1/T2: 4.7%, T2/T2: 0.0%, p = 0.02 in a multivariable regression model). The total number of mutated T2-alleles present in a mother/child pair was associated with a reduction of TTN (4 T2-alleles: 6.4%, n=95; 3: 5.9%, n=30; 2: 3.1%, n=9; 1: 1.4%, n=1; 0:0%, n=0; p < 0.01 in a multivariable regression model). CONCLUSIONS: Both the maternal and fetal mutated alleles of the PROGINS progesterone receptor polymorphism seem to protect from TTN. The same phenotype occurs regardless of whether the mutation is localized in the mother or in the infant. Fetal as well as maternal T2-alleles synergistically reduce the risk for TTN in a gene dose-dependent manner.

New evidence for the fetal insulin hypothesis: fetal angiotensinogen M235T polymorphism is associated with birth weight and elevated fetal total glycated hemoglobin at birth.

BACKGROUND: Low birth weight is associated with an increased risk of cardiovascular events in later life. Insulin resistance is a key finding in adult patients with cardiovascular diseases. The neonatal phenotype of an individual with insulin resistance might be low birth weight, as insulin influences fetal growth. The renin-angiotensin-aldosterone system has been associated with cardiovascular disease and insulin resistance. We analyzed whether fetal polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme genes influence birth weight and/or fetal total glycated hemoglobin (fTGH), a surrogate parameter of fetal insulin resistance at birth. METHOD: In 1132 white women delivering singletons, neonatal umbilical blood samples and clinical data of the mothers and newborns were obtained. Newborns were genotyped with respect to the AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism. RESULTS: The AGT M235T TT polymorphism is associated with reduced birth weight (TT: 3288 g versus TM + MM: 3435 g, P < 0.05). Furthermore, newborns with a high percentage of fTGH (>6.5%) are more likely to have the TT genotype than those with normal fTGH (

Interaction of maternal peroxisome proliferator-activated receptor gamma2 Pro12Ala polymorphism with fetal sex affects maternal glycemic control during pregnancy.

It was suggested that fetal sex may substantially affect maternal glycemic control during pregnancy in genetically susceptible mothers. The peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism is known to affect glycemic control and may act in a sex-specific manner. This polymorphism is thus an attractive candidate to test this hypothesis using a second independent functionally relevant polymorphism. We analyzed the impact of fetal sex on maternal glycemic control during pregnancy in relation to the maternal PPARgamma2 Pro12Ala polymorphism. Two-thousand fourteen Caucasian women without preexisting diabetes and preexisting hypertension with singleton pregnancies delivering consecutively at the Charité obstetrics department were genotyped. Glycemic control was analyzed by measuring total glycated hemoglobin at birth. Correction for confounding factors and multiple testing was considered in the analysis. The maternal PPARgamma2 Pro12Ala polymorphism without consideration of fetal sex had no effect on blood pressure, new onset of proteinuria and total glycated hemoglobin at delivery. Mothers carrying both G alleles (GG genotype) delivering a girl had a higher (P = 0.015) total glycated hemoglobin (6.81 or - 0.50%) versus mothers carrying the same alleles but delivering boys (5.85 + or - 0.58%). Comparing mothers with the GG genotype delivering girls with mothers with CC or CG genotypes also delivering girls (6.32 + or - 0.72%) revealed a significantly higher maternal total glycated hemoglobin at delivery in the former group (P < 0.009). Fetal sex/sex chromosomes may substantially affect maternal glycemic control in mothers who are carriers of the GG alleles of the PPARgamma2 Pro12Ala polymorphism.

Early subcutaneous administration of etanercept (Enbrel) prevents from hyperoxia-induced lung injury.

Both hyperoxia-induced proapoptotic sensitization of alveolar type II cells (TII cells) and high-stretch mechanical ventilation induced pulmonary inflammation are tumor necrosis factor alpha (TNFalpha) mediated. Therefore, binding of free TNFalpha should protect from TNFalpha-mediated acute lung injury and ameliorate the subsequently developing chronic lung disease. Here, the authors show that a single subcutaneous pretreatment of rat with etanercept, a recombinant p75 TNF receptor 2 human immunoglobulin G1 (IgG1) construct, inhibits the hyperoxia-induced and TNFalpha-mediated increase in the expression of TNFalpha receptor, the activation of caspase 3 in TII cells, and, as an early indicator of lung injury, the capillary-alveolar leakage and granulocyte number in lung lavage. The authors assume that subcutaneous administration of etanercept might be suitable to prevent acute lung injury and its sequelae induced by hyperoxic ventilation of premature neonates and critically ill patients.

Vascular endothelial growth factor as marker for tissue hypoxia and transfusion need in anemic infants: a prospective clinical study.

OBJECTIVE: Oxygen-carrying capacity of blood is reduced in anemic infants because of low hemoglobin levels. Red blood cell transfusions become necessary if low hematocrit causes tissue hypoxia. No reliable parameters exist for detecting chronic tissue hypoxia. Vascular endothelial growth factor is upregulated by hypoxia; hence, elevated vascular endothelial growth factor levels may be a marker for tissue hypoxia and may indicate the need for red blood cell transfusions. METHODS: In a prospective study, plasma vascular endothelial growth factor levels were measured in 3 groups of infants suspected of requiring red blood cell transfusions to find a vascular endothelial growth factor cutoff value indicative of tissue hypoxia. The 3 groups were acute anemic (an episode of acute bleeding [hematocrit drop > 5%] per day); chronic anemic (hematocrit drop < 5% per day); and nontransfused (hematocrit drop < 5% per day) but not meeting clinical criteria for a transfusion. Blood was sampled before transfusion and again 48 hours after transfusion if required. Plasma vascular endothelial growth factor and erythropoietin concentrations were measured. RESULTS: Vascular endothelial growth factor concentrations were lower in acutely anemic compared with chronically anemic infants, whereas erythropoietin levels did not differ between these groups. The vascular endothelial growth factor concentration was <140 pg/mL in all acutely anemic infants, and this was deemed the threshold level indicating sufficient tissue oxygenation in subsequent analysis. We found that 30% of chronically anemic and 43% of nontransfused infants had vascular endothelial growth factor levels of >140 pg/mL. In transfused infants, with elevated vascular endothelial growth factor levels, red blood cell transfusion resulted in lowering of vascular endothelial growth factor concentrations. CONCLUSIONS: Vascular endothelial growth factor concentrations of >140 pg/mL may indicate insufficient oxygen delivery to tissues and may serve as a marker of the need for transfusion or of tissue hypoxia in other diseases.

Trefoil factors in human milk.

We measured concentrations of the gastrointestinal protective peptides Trefoil factors in human milk. By the use of in-house ELISA we detected high amounts of TFF3, less TFF1 and virtually no TFF2 in human breast milk obtained from 46 mothers with infants born extremely preterm (24-27 wk gestation), preterm (28-37 wk gestation), and full term (38-42 wk gestation). Samples were collected during the first, second, third to fourth weeks and more than 4 wks postpartum. Median (range) TFF1 [TFF3] concentrations in human milk were 320 (30-34000) [1500 (150-27,000)] pmol/L in wk 1, 120 (30-720) [310 (50-7100)] pmol/L in wk 2, 70 (20-670) [120 (20-650)] pmol/L in wks 3 to 4, and 60 (30-2500) [80 (20-540)] pmol/L in >4 wks after delivery. The lowest concentrations of TFF1 and TFF3 were found later than 2 wks after birth. In conclusion, TFF was present in term and preterm human milk with rapidly declining concentrations during the first weeks post partum. The clinical significance of TFF present in human milk remains to be explored, both regarding development of the fetal gut and protection against necrotizing enterocolitis.

Formation of reactive oxygen species in lung alveolar cells: effect of vitamin E deficiency.

Reactive oxygen species (ROS) play an important role in the pathogenesis of numerous pulmonary diseases. Various mainly membrane-bound ROS-generating processes exist in alveolar cells. Vitamin E (vit. E) is the most important lipophilic antioxidant. However, the significance of vit. E levels in alveolar cells for the regulation of ROS generation has not been investigated so far. We demonstrated here that feeding rats with vit. E-depleted nourishment for 5 weeks reduced the concentration of vit. E in alveolar type II cell preparations to one-fifth the amount of control animals. This reduction of vit. E levels was associated with an approximately threefold increase in ROS generation in type II pneumocytes, lymphocytes, and macrophages. The contribution of individual processes of ROS formation in control animals differed strongly among these three cell types. However, vit. E deficiency induced predominantly nonmitochondrial ROS formation in alveolar cells. Expression and NAD(P)H-oxidase activity in alveolar type II cell preparations was not affected by vit. E deficiency. Moreover, protein kinase C (PKC) also did not seem to be responsible for vit. E deficiency-induced ROS generation in alveolar cells. Alimentary vit. E supplementation for 2 days corrected the cellular vit. E concentration but failed to normalize ROS generation in alveolar cells. These data let us assume that alimentary vit. E deficiency caused a preferentially nonmitochondria-mediated increase of ROS formation in type II pneumocytes, macrophages, and lymphocytes. However, the short-term supplementation of vit. E does not reverse these effects.

Impact of maternal angiotensinogen M235T polymorphism and angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure, protein excretion and fetal outcome in pregnancy.

OBJECTIVE: To test the hypothesis that genetically determined alterations of the renin-angiotensin system are associated with hypertensive disorders in pregnancy. METHODS: A genetic association study was conducted at the obstetrics department of the Charité university hospital, Berlin, Germany. A total of 1068 Caucasian women were consecutively included after delivery and genotyped for the angiotensinogen M235T polymorphism and the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism. RESULTS: Women homozygous for the angiotensinogen T allele have significantly elevated mean systolic and diastolic blood pressures in the third trimester (118.4 +/- 1.1/71.5 +/- 0.7 versus 116.9 +/- 0.3/70.4 +/- 0.2 mmHg, n = 128 versus 940; P < 0.05). This finding is especially pronounced in the subgroup of primigravid women. The ACE polymorphism is not associated with blood pressure during pregnancy. None of the polymorphisms is associated with urinary protein excretion or oedema during pregnancy. Maternal polymorphisms do not influence fetal growth and birth weight. There is, however, an interesting trend towards an increased incidence of circulatory system malformations in newborns carrying alleles that are known to be associated with decreased intrinsic renin-angiotensin system activity. CONCLUSION: We demonstrate for the first time in a large Caucasian population that a common maternal polymorphism of the angiotensinogen gene is related to a blood pressure increase during pregnancy. The angiotensinogen M235T polymorphism might contribute to the multifactorial pathogenesis of gestational hypertension and pre-eclampsia.