Influence of smoking and alcohol during pregnancy on outcome of VLBW infants.

BACKGROUND: Nicotine and alcohol consumption have been associated with premature delivery and adverse neonatal outcome. We wanted to analyze the influence of self-reported nicotine and alcohol consumption on outcome of VLBW infants. MATERIAL AND METHODS: In an ongoing multicenter study 2475 parents of former very low birth weight (VLBW) infants born between January 2009 and December 2011 answered questionnaires about maternal smoking habits and alcohol consumption during pregnancy. 2463 (99.5%) completed questions on alcohol consumption and 2462 (99.5%) on smoking habits. These infants were stratified to reported maternal smoking and alcohol consumption during pregnancy. We compared the reasons for premature delivery, neonatal outcome and parental reports on bronchitis during the first year of life, as well as growth and development at age 2 years to pregnancy exposure. RESULTS: In nicotine exposed infants intrauterine growth restriction (31 vs. 21%, p<0.01), a birth weight below the 10th percentile (26 vs. 17%, p<0.01) and placenta abruption (9.2 vs. 5.8%, p<0.05) was seen more often. Premature rupture of membranes (24 vs. 30%, p<0.05) or HELLP syndrome (6 vs. 11%, p<0.01) was less frequent. A birth weight below the 3rd percentile was seen more frequently in mothers with reported alcohol consumption (13 vs. 6%, p<0.05). We noted an increased rate of BPD and ROP if mothers reported smoking during pregnancy (p<0.05). Growth parameters and scores on Bayley Sscales of infant development at age 2 years did not differ. CONCLUSION: Smoking during pregnancy results in a high rate of growth restricted VLBW infants. Prenatal exposition to nicotine seems to increase postnatal complications such as BPD und ROP.

[Ophthalmological screening for retinopathy of prematurity]. / Augenärztliches Screening bei Frühgeborenen.

Retinopathy of prematurity (ROP) is one of the three leading causes of legal blindness in childhood in developed countries. Adequate screening is one of the most important steps towards successful treatment. During the last decades, international and national guidelines for ROP screening have been continually updated. These guidelines correspond to progress in neonatal care and to a better understanding of the relationship between different neonatal parameters and the risk of developing ROP. The present article surveys ROP classification, the current national and international guidelines and new aspects of ROP screening.

[Scrotal ultrasound in children and adolecents with duplex Doppler analysis of intratesticular arteries]. / Hodensonografie bei Kindern und Jugendlichen mit Bestimmung Doppler-sonografischer Referenzwerte der intratestikulären Arterien.

PURPOSE: Scrotal ultrasound, color Doppler and spectral Doppler analysis of intratesticular arteries are the most common and important examinations in boys with scrotal pain. In the existing literature information concerning feasibility and reference values of color Doppler and spectral Doppler in small testes is inconsistent. MATERIALS AND METHODS: In the present study 102 boys from 2 days to 16 years old without present or anamnestic scrotal disease were examined in a standardized manner. Using linear scanners (9 - 14 mHz), testicular volumetry and spectral Doppler analysis of typical intratesticular arteries were performed and the paratesticular structures were examined. For analysis we grouped the testes by volume and compared the measured values V. max syst., V. max enddiast., and RI. RESULTS: In all test subjects a complete examination with spectral Doppler analysis of intratesticular arteries could be performed. With increasing testicular volume, there is a linear increase in blood flow velocities V. max syst. and V. enddiast. Irrespective of age and testicular volume, the RI of the intratesticular arteries is 0.54 ± 0.08. CONCLUSION: In contrast to published data, this study shows that color Doppler and spectral Doppler of testicular arteries can be regularly performed even in small testes of less than 1 ml. Reference values for blood flow velocities and RI were found and should improve the diagnostic value of testicular ultrasound examinations in children.

Impact of parvovirus B19 infection on paediatric patients with haematological and/or oncological disorders.

To determine the frequency and the impact of parvovirus B19 (B19V) infection and its influence on the course of haematological and/or oncological diseases in paediatric patients, consecutive serum and bone marrow samples from 110 were analyzed for markers of acute, past and persistent B19V-infection using qPCR, ELISA and WesternLine. Twenty-seven out of 110 (24.5%) children suffered from non-malignant diseases (anaemia, pancytopenia, autoimmune disorders); 68/110 (61.8%) patients had developed leukaemia, malignant lymphoma or solid malignant tumours; 15/110 patients (13.6%) presented with other symptoms. At admission, B19V-specific IgM and IgG indicating acute or previous B19V-infection were observed in 5 (4.5%) and 48 patients (43.6%), respectively. B19V-DNA (10(3) -10(9) geq/mL) was detectable in serum and/or bone marrow of 22 patients (20.0%). These suffered from leukaemia (5), non-Hodgkin lymphoma (2), solid tumours (6), autoimmune (4) and haematological (4) disease and fever (1). During clinical observation four further leukaemia patients developed viraemia and persistent B19V-infection was observed in 13/22 DNA-positive patients. Treatment of B19V-DNA-positive cancer patients was associated with more supportive therapy involving erythrocyte and thrombocyte transfusion and/or antibiotic therapy. Acute B19V-infection has been frequently observed in paediatric patients with haematological and/or oncological disease. In patients with non-malignant diseases anaemia or autoimmune disorders were diagnosed in association with B19V-infection. Furthermore, a significant number of cancer patients displayed markers for acute, recent or persistent B19V-infection. This association may be strengthened by frequent treatment with blood products combined with therapeutic immune suppression. In B19V-infected cancer patients supportive therapy was more complex.

Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues.

In all known congenital imprinting disorders an association with aberrant methylation or mutations at specific loci was well established. However, several patients with transient neonatal diabetes mellitus (TNDM), Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) exhibiting multilocus hypomethylation (MLH) have meanwhile been described. Whereas TNDM patients with MLH show clinical symptoms different from carriers with isolated 6q24 aberrations, MLH carriers diagnosed as BWS or SRS present only the syndrome-specific features. Interestingly, SRS and BWS patients with nearly identical MLH patterns in leukocytes have been identified. We now report on the molecular findings in DNA in three SRS patients with hypomethylation of both 11p15 imprinted control regions (ICRs) in leukocytes. One patient was a monozygotic (MZ) twin, another was a triplet. While the hypomethylation affected both oppositely imprinted 11p15 ICRs in leukocytes, in buccal swab DNA only the ICR1 hypomethylation was visible in two of our patients. In the non-affected MZ twin of one of these patients, aberrant methylation was also present in leukocytes but neither in buccal swab DNA nor in skin fibroblasts. Despite mutation screening of several factors involved in establishment and maintenance of methylation marks including ZFP57, MBD3, DNMT1 and DNMT3L the molecular clue for the ICR1/ICR2 hypomethylation in our patients remained unclear. Furthermore, the reason for the development of the specific SRS phenotype is not obvious. In conclusion, our data reflect the broad range of epimutations in SRS and illustrate that an extensive molecular and clinical characterization of patients is necessary.

Surfactant without intubation in preterm infants with respiratory distress: first multi-center data.

BACKGROUND: Recently in a report of a single center a method has been described to apply surfactant via a thin endotracheal catheter to very low birth weight infants spontaneously breathing with nasal continuous positive airway pressure. We now analyzed available multicenter data. PATIENTS AND METHODS: In a multicenter study investigating genetic risk factors, clinical and outcome data and data of antenatal and postnatal treatment of infants with a birth weight below 1,500 g were prospectively recorded. The measures of infants treated with the new method of surfactant application were compared to those of infants who received standard care. The analysis was restricted to infants with a gestational age below 31 weeks (n=1,541). RESULTS: 319 infants were treated with the new method and 1,222 with standard care. The need for mechanical ventilation during the first 72 h (29% vs. 53%, p<0.001), the rate of bronchopulmonary dysplasia defined as oxygen at 36 weeks of postmenstrual age (10.9 % vs. 17.5%, p=0.004) and the rate of death or bronchopulmonary dysplasia were significantly lower in the treatment group than in the standard care group. Surfactant, theophyllin, caffeine and doxapram were significantly more often and analgetics, catecholamines and dexamethasone were significantly less frequently used in the treatment group. CONCLUSIONS: A new method of surfactant application was associated with a lower prevalence of mechanical ventilation and better pulmonary outcome. A prospective controlled trial is required to determine whether this approach is superior to standard care.

Polymorphisms in the Renin-Angiotensin system and outcome of very-low-birthweight infants.

BACKGROUND: The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE-ins/del) and the angiotensin II type 1 receptor 1166A/C polymorphism (ATR1166A/C) were reported to be associated with several unfavorable outcome parameters in preterm infants like bronchopulmonary dysplasia, persistent ductus arteriosus and impaired insulin sensitivity. OBJECTIVE: To confirm the above-mentioned associations in a large cohort of very-low-birthweight (VLBW) infants. METHOD: Clinical data of VLBW infants were prospectively recorded. The ACE-ins/del polymorphism and the ATR1166A/C polymorphism were determined by polymerase chain reaction in 1,209 and 1,168 infants, respectively. RESULTS: There was no significant association between ACE-ins/del or ATR1166A/C genotype and outcome parameters (death, intraventricular hemorrhage, sepsis, bronchopulmonary dysplasia, ventilation, supplemental oxygen at discharge, postnatal treatment with insulin, surgery for intestinal perforation/necrotizing enterocolitis/retinopathy of prematurity/persistent ductus arteriosus. CONCLUSION: Both known functional polymorphisms of the renin-angiotensin system do not seem to be associated with the outcome of VLBW infants.

Prevalence and clinical aspects of human bocavirus infection in children.

Human bocavirus (HBoV) was recently described as a new member of the Parvoviridae. In order to investigate the suggested association of HBoV with respiratory and gastric disease in infants and young children, sera of 357 paediatric patients hospitalized with infectious and non-infectious diseases were retrospectively analyzed for the presence of HBoV DNA and virus-specific antibodies using quantitative PCR and ELISA, respectively. HBoV seroprevalence was determined to range from 25% in infants younger than 1 year of age to 93% in children aged more than 3 years. Viral loads between 1 x 10(2) and 1.2 x 10(6) geq/mL were observed in 6.7% (20/297) of sera obtained preferentially from young children suffering from infectious diseases. HBoV genomes were furthermore detected in 5% (3/60) of sera collected from individuals with non-infectious illnesses. HBoV DNA was present most frequently in patients with respiratory disease (9.6%). Whereas only 5.2% of patients with upper respiratory tract disease were viraemic, HBoV DNA was found in 14.6% and 10.0% of patients with lower respiratory tract illness and pneumonia, respectively. Acute HBoV infections were also observed in 7.5% of patients with gastroenteritis and in one child with inflammatory bowel disease. None of 77 patients hospitalized for various other infectious diseases (e.g. rash, urinary tract infection, meningitis) displayed viraemia. In 60.9% and 47.8% of DNA-positive children, HBoV-specific IgM and IgG was observed, respectively. The present prospective study provides comprehensive data on the clinical association of acute HBoV infection with respiratory illness and on the seroprevalence of virus-specific antibodies in children.

[A young infant with afebrile pneumonia caused by Chlamydia trachomatis]. / Chlamydia trachomatis als Erreger einer afebrilen Pneumonie beim jungen Säugling.

Pregnant women who have an urogenital Chlamydia trachomatis infection may transmit the infection to their infants. Conjunctivitis and nasopharyngeal infection are the most frequent manifestations. Less frequently the infants may develop pneumonia. We report a case of a 5-week-old girl with poor feeding, staccato cough and clinical signs of pneumonia. Chest radiography revealed severe bronchopneumonia. Despite of intravenous therapy with ampicillin and gentamicin respiration deteriorated and oxygen supplementation became necessary. After additional treatment with oral erythromycin (50 mg/kg per day) had been started the clinical condition improved. Polymerase chain reaction with a nasopharyngeal specimen was found to be positive for Chlamydia trachomatis.

Interleukin-6-174-genotype, sepsis and cerebral injury in very low birth weight infants.

We investigated the association between the interleukin 6 (IL-6)-174-genotype and unfavorable outcomes in preterm infants since it has been reported that the IL-6-174GG-genotype is associated with increased susceptibility to sepsis, and the IL-6-174CC-genotype is more common in preterm infants with severe intraventricular hemorrhage (IVH). We studied 1206 preterm infants with a birth weight below 1500 g. In contrast to previously published data, the frequency of IVH grade IV, periventricular leukomalacia, ventricular-peritoneal-shunting or death was not different between infants with different IL-6-genotypes: IL-6-174GG (n = 430) 8%, IL-6-174GC (n = 605) 9% and IL-6-174CC (n = 167) 12% (P = 0.2 for IL-6-174CC vs GG + GC). Furthermore, we were not able to confirm previously reported association between sepsis and the IL-6-174GG-genotype. Blood-culture-proven sepsis occurred in 19% of IL-6-174GG-carriers (n = 157), 26% of IL-6-174GC-carriers (n = 193) and 27% of infants carrying the IL-6-174CC-genotype (n = 67). We were not able to confirm previously reported associations between sepsis, cerebral injury and the IL-6-174-genotype in VLBW-infants.

Polymorphisms of genes involved in innate immunity: association with preterm delivery.

An altered inflammatory activity due to functionally relevant polymorphisms of the innate immune system may influence pathways leading to labour and, therefore, impact on the frequency of preterm birth. We examined five polymorphisms of the innate immune system in a large cohort of preterm very-low-birth-weight (VLBW, n = 909) and term-born infants (n = 491) and their mothers (n = 747). The primary outcome was preterm versus term birth. Frequencies of polymorphisms in mothers of term-born infants versus mothers of VLBW infants and term infants versus preterm VLBW infants (singletons) are given. Homozygous CD14-159T: 18.5 versus 21.8% (mothers) and 19.6 versus 21.2% (infants). Homozygous interleukin IL-6-174G: 28.8 versus 38% (P = 0.018, mothers) and 30 versus 32.7% (infants). Homozygous or heterozygous nuclear oligomerization domain NOD2-3020insC: 6.9 versus 6.1% (mothers) and 5.7 versus 5.1% (infants). Heterozygous or homozygous toll-like-receptor TLR2-Arg753Gln: 6.9 versus 6.1% (mothers) and 5.7 versus 5.1% (infants). Homozygous or heterozygous TLR4-896G: 8.1 versus 11.5% (mothers) and 11.6 versus 10.5% (infants). Although the homozygous maternal IL-6-174G genotype was found to be independently associated with preterm delivery in multivariate regression analysis, the incidence of intrauterine infection was not significantly increased in mothers of preterm VLBW-infants, carrying this or other polymorphisms of the innate immune system. The overall influence of the investigated polymorphisms on the development of preterm delivery seems moderate, since only the maternal IL6-174G genotype was associated with preterm birth and none of the polymorphisms were associated with intrauterine infection as the cause of preterm birth.

A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia.

Fibroblast growth factor receptor 3 (FGFR3) is a glycoprotein that belongs to the family of tyrosine kinase receptors. Specific mutations in the FGFR3 gene are associated with autosomal dominant human skeletal disorders such as hypochondroplasia, achondroplasia, and thanatophoric dysplasia. Hypochondroplasia (HCH), the mildest form of this group of short-limbed dwarfism disorders, results in approximately 60% of cases from a mutation in the intracellular FGFR3-tyrosine kinase domain. The remaining cases may either be caused by defects in other FGFR gene regions or other yet unidentified genes. We describe a novel HCH mutation, the first found outside the common mutation hot spot of this condition. This point mutation, an N328I exchange in the extracellular Ig domain III of the receptor, seems to be unique as it affects a putative N-glycosylation site that is conserved between different FGFRs and species. The amino acid exchange itself most probably has no impact on the three-dimensional structure of the receptor domain, suggesting that the phenotype is the result of altered receptor glycosylation and its pathophysiological consequences.

[Skin changes in newborn infants in the first 5 days of life]. / Hautveränderungen bei Neugeborenen in den ersten 5 Lebenstagen.

BACKGROUND AND OBJECTIVE: To prospectively survey skin lesions in a large group of newborns, as no such study has as yet been performed in Germany. PATIENTS/METHODS: In a prospective study, we examined one thousand newborn babies twelve to 120 hours old. RESULTS: In 59.7%, one or more skin lesions could be detected, some of which were only transient. Noticeable differences from other studies included a higher incidence of congenital melanocytic nevi (6%) and port wine stains (2.8%). Instead of the usual male:female ratio of 1:2 we found a 1:1 ratio for port wine stains. Toxic erythema of the newborn and milia were less frequent than in other studies. CONCLUSIONS: With a frequency of 37.2%, vascular lesions such as nevus flammeus and hemangioma are the most common skin lesions in newborns. Our study found a higher incidence of congenital melanocytic nevi than reported in literature. An associated of skin lesions and maternal smoking during pregnancy was not detected.

Follow-up findings in regional cerebral blood flow (r-CBF)-SPECT in a case of idiopathic childhood hemidystonia. Functional neuroimaging and pathophysiological implications.

A 9 1/2-year-old girl suffered from intermitting tremor and jitteriness of her left hand and oral muscles every 4 to 6 weeks with long lasting episodes. Clinically myoclonias and dystonic positioning of the left arm, hand and facial muscles were seen. No evidence of trauma, infection or inborn errors of metabolism was found. Successful therapy with carbamazepine was initiated while L-DOPA failed. An ictal 99m-Tc-HMPAO-SPECT showed severe asymmetry with focal hyperperfusion of the contralateral right thalamus and basal ganglia as well as of the bifrontal cortex, whereas no anatomical lesions were found by MRI. In contrast, an interictally performed 99m-Tc-HMPAO SPECT showed hypoperfusion of the right thalamus and normalisation of the frontal perfusion under medical treatment. These 99m-Tc-HMPAO-SPECT findings may provide new insights into the localisation and pathophysiological pathways of idiopathic childhood dystonia.

Circulatory changes after surfactant bolus instillation in lung-lavaged adult rabbits.

Following surfactant instillation in infants treated for respiratory distress syndrome, a mean arterial blood pressure (MABP) decrease is often observed. Its etiology and pathogenesis are still unknown. In this study various circulatory parameters were recorded continuously after surfactant instillation to elucidate the role of pulmonary vascular resistance as one possible cause for the MABP drop. Seven anesthetized adult New Zealand white rabbits were artificially ventilated after tracheotomy. Arterial and right atrial pressure were recorded continuously. Pulmonary artery pressure and cardiac output were determined by means of a thermodilution catheter. After inducing surfactant deficiency by repeated saline lavages, 200 mg/kg body weight of a natural surfactant preparation was administered by tracheal bolus instillation. PaO2 increased rapidly from 8.0 +/- 1.3 kPa to 51.2 +/- 8.8 kPa (mean +/- standard deviation) within 2 min (p < .05). MABP dropped from 12.1 +/- 1.9 kPa to 8.9 +/- 2.3 kPa within 2 min (p < .05). Pulmonary artery pressure, cardiac output, and right atrial pressure did not change during the observation period of 60 min. The results suggest that a peripheral vasodilatation is the most likely cause for the drop in MABP.

Rapid tracheal infusion of surfactant versus bolus instillation in rabbits: effects on oxygenation, blood pressure and surfactant distribution.

UNLABELLED: Surfactant bolus instillation may be associated with a drop in blood pressure. Platelet-activating factor (PAF) has been found in surfactant preparations. The aim of this study was to evaluate rapid tracheal infusion of surfactant during 5 min as an alternative to bolus instillation and to examine whether a PAF receptor antagonist is able to prevent the decrease in blood pressure. METHODS: Surfactant deficiency was induced in 16 adult rabbits by lung lavages with saline. Six animals received a bolus of a porcine surfactant preparation (Curosurf (CS); 200 mg/kg), labeled with red microspheres to assess pulmonary distribution. In another 5 rabbits, the same amount of labelled CS was instilled by tracheal infusion within 5 min. A third group of 5 animals received 3 mg/kg body weight of the PAF antagonist WEB 2170 before CS bolus instillation. RESULTS: After CS bolus administration, mean PaO2 increased by 44.7 +/- 8.3 kPa (mean +/- SD) within 2 min and remained at this level. Mean arterial blood pressure dropped transiently by 2.3 +/- 2 kPa within 5 min. Pulmonary distribution of surfactant was even. After infusion, mean PaO2 rose by 22.4 +/- 16.3 kPa within 15 min. Blood pressure dropped by 1.8 +/- 1.1 kPa within 15 min. The distribution was extremely uneven. Blood pressure decreases also occurred after pretreatment with PAF receptor antagonist. CONCLUSION: Rapid tracheal infusion of surfactant results in poorer oxygenation, an inhomogeneous distribution and a similar decrease in blood pressure compared to the bolus instillation method. Blood pressure changes could not be prevented by a PAF receptor-specific antagonist.

Surfactant bolus instillation: effects of different doses on blood pressure and cerebral blood flow velocities.

Fifteen preterm infants suffering from respiratory distress syndrome were randomly allocated to receive either high-dose (200 mg/kg) or low-dose (100 mg/kg) surfactant treatment. Retreatments were done with the low dose. Blood pressure, blood gases and cerebral blood flow velocities were determined before and after 24 bolus instillations. With the high dose mean blood pressure and mean cerebral blood flow velocity dropped significantly. With the low dose only mean cerebral blood flow velocity decreased; the course was unrelated to blood pressure or PCO2 fluctuations. The mechanisms leading to the observed circulatory changes after surfactant instillation remain unclear.

Pulmonary distribution and efficacy of exogenous surfactant in lung-lavaged rabbits are influenced by the instillation technique.

Surfactant bolus instillation has been reported to cause changes in arterial blood pressure (BP) and cerebral blood flow velocities which may increase the risk of intraventricular haemorrhage. To avoid these effects, slow tracheal infusion was evaluated as a possible alternative method of surfactant administration. Saline lung lavages were performed in 13 anesthetized and artificially ventilated adult rabbits to produce respiratory distress syndrome. Curosurf (CS, 200 mg/kg) labeled with 14C-dipalmitoyl-phosphatidylcholine (-DPPC) and/or red microspheres (RMS) was instilled into the trachea either as a single bolus (n = 8) or by infusion during 45 min via a side-channel within the wall of the tracheal tube (n = 5). An arterial cannula was placed for monitoring of blood gases and BP. To determine surfactant distribution, the lungs were cut into 60-70 pieces and radioactivity and/or the number of RMS were measured in each piece. The distribution of RMS was closely related to the distribution of 14C-DPPC (r = 0.96). Bolus instillation of CS led to a prompt and sustained increase in PaO2 (from < 10.5 to > 40 kPa within 2 min), a transient decrease in BP, and a reasonably homogeneous pulmonary surfactant distribution. Tracheal infusion of CS changed neither BP nor PaO2 during the observation period of 60 min. The pulmonary distribution of CS was extremely uneven after infusion. The distribution of exogenous surfactant and its effects on gas exchange are influenced by the instillation method. An inadequate instillation technique may add to the causes of "poor response" after surfactant replacement.

Increased cerebral blood flow velocities in newborn infants of smoking mothers.

Cerebral blood flow velocities (CBFV) were measured by the pulsed Doppler method in 41 infants of smoking mothers and in 59 apparently healthy control infants. Although gestational age, birth weight, and systolic blood pressure were lower in infants exposed to tobacco smoke prenatally, systolic (65 +/- 11 vs. 47 +/- 12 cm/s, mean +/- SD; P < 0.001), mean (36 +/- 6 vs. 25 +/- 6 cm/s; P < 0.001), and diastolic (17 +/- 4 vs 13 +/- 4 cm/s; P < 0.001) CBFVs in the anterior cerebral artery were significantly higher when compared to control infants. Similar differences were seen in the internal carotid and in the basilar arteries. Multiple regression analysis did not reveal differences other than maternal smoking to explain these observations. We conclude that prenatal tobacco smoke exposure is related to increased CBFVs in newborn infants. Further studies should determine whether this relation is not only statistical but causal and whether increased CBFVs are an indicator of prolonged effects of prenatal tobacco smoke exposure.