IVH in VLBW Preterm Babies - Therapy with Recombinant Activated F VII?

Backround Intraventricular hemorrhage (IVH) remains a dangerous and frequent complication in very low birth weight (VLBW) infants. Activated factor VII (aFVII) activates the coagulation cascade and is a potential tool for stopping active bleeding, including limiting the extent of an IVH. This retrospective treatment observation compared data for infants with IVH progression treated with fresh frozen plasma (FFP) alone or with a combination of FFP and aFVII. Methods/Intervention All infants were subject to cranial ultrasonography at least twice daily. When an IVH was detected, treatment with FFP (5-20 ml/kg every 4-6 h) was commenced and the parents were informed. If the parents endorsed aFVII treatment and the IVH showed progress, aFVII (30-50 µg/kg body weight 4-6 times within 16-24 h) was given. Otherwise, infants were treated with FFP only. We compared the course of IVH between the aFVII+FFP treated infants and a control group (FFP only). Results 35 patients throughout were included in the analysis (17 control and 18 aFVII group). Demographic data was not different between groups. The progress of IVH was significantly less in the aFVII group (p<0.01). During the hospital stay, 2 of the infants in the aFVII group died compared to 4 in the control group. A posthemorrhagic hydrocephalus developed in 3 aFVII and 6 control infants. All other outcome parameters and follow-up-results 2 years after treatment did not differ significantly. Conclusion These data show that in the case of a progressing IVH, aFVII may be a candidate for limiting its extent. A prospective randomized trial is warranted.

Incorporating anti-infective drugs into peripherally inserted catheters does not reduce infection rates in neonates.

Purpose: This study assesses whether peripherally inserted central venous catheters (PICC), impregnated with anti-infective drugs, reduce the rate of infections in neonates compared with unimpregnated catheters. Methods: A retrospective analysis was conducted on electronic patient records of neonates born between August 2014 and May 2020, who had PICCs inserted, either standard (S-PICC) or with anti-infective drugs (A-PICC). Catheter-related bloodstream infections (CRBSI) were diagnosed based on clinical symptoms, laboratory results, and mentioning of infection in the patient record. Data on dwell time, mechanical ventilation, insertion site, maximum C-reactive protein (CRP) concentration, and anti-infective drug use were analyzed. Results: A total of 223 PICCs were included. The infection rates were A-PICC (18.9%) and S-PICC (12.5%), which were not significantly different (p = 0.257). A-PICCs had significantly longer dwell times than S-PICCs (median 372 vs. 219 h, p = 0.004). The time to infection was not different between the groups (p = 0.3). There were also no significant differences in maximum CRP, insertion site abnormalities, or anti-infective drug use between the groups. Conclusion: This retrospective study did not find a significant reduction in infection rates by using PICCs containing anti-infective drugs in neonates. Current antibiotic impregnations do not seem to be effective in preventing blood stream infections.

Thyroid gland development and defects.

During the functional ontogenesis of the thyroid gland an increasing number of transcription factors play fundamental roles in thyroid-cell differentiation, maintenance of the differentiated state, and thyroid-cell proliferation. The early growth and development of the fetal thyroid appears to be generally independent of thyroid-stimulating hormone (TSH). TSH and thyroxine (T4) levels increase from the 12th week of gestation until delivery, whereas triiodothyronine (T3) levels remain relatively low. At birth, a cold-stimulated short-lived TSH surge is observed, followed by a TSH decrease until day 3 or 4 of life by T4 feedback inhibition. Disorders of thyroid gland development and/or function are relatively common, affecting approximately one newborn infant in 2000-4000. The most prevalent disease, congenital hypothyroidism, is frequently caused by genetic defects of transcription factors involved in the development of the thyroid or pituitary gland. A major cause of congenital hyperthyroidism is the transplacental passage of stimulating thyrotropin antibodies from the mother to the fetus. Hypothyroxinaemia or hypotriiodthyroninaemia is frequently observed in preterm infants with or without severe non-thyroidal illness. Whereas congenital hypo- and hyperthyroidism may be treated successfully with T4 or thyrostatic drugs, there is still insufficient evidence on whether the use of T4 for treatment of the latter condition results in changes in neonatal morbidity or reductions in neurodevelopmental impairment.

Antifungal Treatment and Outcome in Very Low Birth Weight Infants: A Population-based Observational Study of the German Neonatal Network.

BACKGROUND: The diagnostic proof of fungal infection in preterm infants is difficult. Antifungal treatment (AFT) is often initiated empirically when infants with suspected infection do not improve despite broad-spectrum antibiotic therapy. It was the aim of our study to determine the rate of exposure to empirical AFT in a large cohort of very low birth weight infants (VLBWI) of the German Neonatal Network and to address associated risks and outcomes. METHODS: The epidemiologic database consisted of n = 13,343 VLBWI born in 54 German Neonatal Network centers between 2009 and 2015. AFT was defined as number of neonates who got any dose of at least one of the following antifungal drugs: fluconazole, amphotericin B, voriconazole and caspofungin (denominator: number of infants enrolled in German Neonatal Network) for treatment (not prophylaxis) of (suspected) fungal infection. Univariate and logistic regression analyses were used to identify risk factors for exposure to AFT and associated short-term morbidities and long-term outcomes at 5-year follow-up. RESULTS: In our cohort, 724 out of 13,343 (5.4%) VLBWI were exposed to empiric AFT and had a mean gestational age of 25.7 (±2.1) weeks. Forty-four out of 13,343 (0.3%) had proven bloodstream infection with Candida spp. The main risk factors for exposure to AFT were gestational age, postnatal steroid treatment, need for abdominal surgery and use of carbapenems. Notably, AFT was associated with adverse outcomes such as bronchopulmonary dysplasia [adjusted odds ratio (OR): 1.9; 95% confidence interval (CI): 1.6-2.3; P < 0.001) and retinopathy of prematurity requiring intervention (adjusted OR: 1.69; 95% CI: 1.3-2.3; P <0.001) but not mortality. In the subgroup of infants available for 5-year follow-up (n = 895), exposure to AFT was associated with a risk for cerebral palsy (adjusted OR: 2.79; 95% CI: 1.11-7.04; P = 0.04) and intelligence quotient < 85 (adjusted OR: 2.07; 95% CI: 1.01-4.28; P = 0.049). CONCLUSIONS: A significant proportion of VLBWI is exposed to AFT, specifically those born <26 weeks. Exposed infants were found to have a higher risk for adverse outcomes, which may reflect their significant vulnerability in general. Given the observational design of our study, it remains unclear whether potential side effects of empirical or target AFT itself contribute to adverse outcome. Future studies need to include risk-based strategies and stewardship programs to restrict the use of antifungal management in VLBWI.

Cardiovascular impact of dobutamine in neonates with myocardial dysfunction.

OBJECTIVE: To study effects of dobutamine on cardiac functional parameters, cerebral, mesenteric and renal blood flow in preterm neonates with myocardial dysfunction. STUDY DESIGN: Prospective evaluation of Doppler sonographically measured left ventricular systolic time intervals, stroke volume (SV), cardiac output (CO), and blood flow parameters of anterior cerebral artery (ACA), superior mesenteric artery (SMA) and renal arteries (RA), before, after 20 min and 8-10 h of dobutamine treatment in 20 neonates (gestational age 29.6+/-4.4 weeks, birth weight 1450+/-609 g and postnatal age 2+/-2.1 days). Dobutamine was given in a mean dosage of 9.1+/-1.1 microg/kg. RESULTS: After 20 min SV increased from 1.71+/-0.5 ml to 2.12+0.57 ml/kg, CO from 223+/-76 to 290 ml/kg/min. A shortening of left ventricular pre ejection period from 86+/-12 to 66+/-13 ms and of the ratio of pre-ejection period/ejection time from 0.52+/-0.12 to 0.40+/-0.11 were observed. Blood flow velocities of ACA increased after 8-10 h: peak systolic flow velocity (PSV) from 19.0+/-6 to 29.6+/-7.1 ms, end diastolic velocity (EDV) from 2.9+/-2.6 to 12.7+/-11.3 ms. PSV of SMA increased from 32.5+/-4.7 to 49.7+/-7.8 ms after 8-10 h, EDV from 8.9+/-8 ms to 20.6+/-6.1 ms. PSV of RA increased from 18.2+/-6.1 ms to 39.9+/-4.8 ms, EDV from 2.2+/-1.2 to 8.2+/-2.1 ms after 8-10 h. The pulsatility indices decreased significantly after 8-10 h: ACA from 2.3+/-0.6 to 1.4+/-0.5, SMA from 1.7 to 1.2 and RA from 2.57 to 1.57. CONCLUSION: Dobutamine improves the cardiac functional parameters already after 20 min and has an influence on the blood flow parameters of ACA, SMA and RA 8-10 h after administration in neonates with myocardial dysfunction.

Serum concentrations of anti-thyroid peroxidase and anti-thyroglobulin antibodies in children and adolescents without apparent thyroid disorders.

OBJECTIVE: The age-dependent prevalence and clinical relevance of anti-thyroid peroxidase (TPOAb) and anti-thyroglobulin (TGAb) antibodies in children and adolescents without thyroid diseases are unknown. The aim of this study was to measure the concentration of these thyroid autoantibodies in a large cohort of hospitalized and out-patient subjects. Additionally, we investigated the correlation of TPOAb and TGAb with thyroid parameters as well as with putative confounding parameters such as standard deviation scores (SDS) of height, BMI-SDS and CRP. METHODS: Serum samples from 841 patients with non-thyroid related diseases between 1 day post partum and 20 years of age were used in a cross-sectional study. TPOAb, TGAb, thyroid parameters (TSH, fT3, fT4 and thyroglobulin) and CRP were measured by the Modular System (Roche, Mannheim). RESULTS: The values of TPOAb and TGAb showed an age-dependent maximum of antibody frequency for both genders during the first year of life with concentrations of 163 IU/mL and 161 IU/mL in the 95th percentile. In girls, a second maximum was observed during puberty with concentrations of 82 IU/mL TPOAb and 582 IU/mL TGAb in the 95th percentile. Both antibodies correlated significantly (p<0.05) with each other, with fT3, fT4, BMI-SDS (only TPOAb) and CRP and TSH (only TGAb). CONCLUSION: The prevalence of TPOAb and TGAb was shown to be age-dependent with increased values in the first year of life and during puberty. The increased "physiological" concentrations of TPOAb and TGAb have to be considered when used as diagnostic indicators of autoimmune thyroid disease in a paediatric population.

Effects of anaemia on haemodynamic and clinical parameters in apparently stable preterm infants.

BACKGROUND: The criteria for erythrocyte transfusion in stable premature infants are currently controversial. Haemodynamic measurements are not common in transfusion practice. The purpose of this study was to determine whether haemodynamic measurements could be helpful as objective criterion for transfusion decisions. We, therefore, evaluated clinical and haemodynamic changes in stable, anaemic, premature infants before and after transfusion using our current blood transfusion protocol based on a haematocrit threshold (<24%) and the neonatologist's discretion. MATERIAL AND METHODS: Stable premature infants with a haematocrit level ≤30% were prospectively enrolled into the study. Cerebral, intestinal and renal blood flow velocities, cardiac function parameters and vital signs were measured up to three times following every routine haematocrit analysis. Moreover, transfused infants were evaluated three more times: directly before transfusion, and 24 hours and 72 hours after transfusion. RESULTS: Thirty-six infants were enrolled and 23 of them were transfused. Subgroup analysis of transfused infants showed a significant decrease in cerebral blood flow velocities, cardiac output and heart rate. These changes persisted after transfusion. In the entire cohort, the degree of anaemia correlated with the increase of cerebral blood flow velocities, heart rate and cardiac output. DISCUSSION: Cerebral blood velocities in the anterior cerebral artery might represent an objective Doppler sonographic criterion indicating the need for transfusion. The measurement of these velocities is non-invasive and quick and easy to perform. However, a randomised, controlled trial is necessary before a formal recommendation can be made.

Metabolic syndrome in children and adolescents--risk for sleep-disordered breathing and obstructive sleep-apnoea syndrome?

The clinical relevance of the term "metabolic syndrome", the definition criteria, and predictive power are being disputed. Inclusion of sleep-disordered breathing and sleep apnoea into a definition of metabolic syndrome is also controversial once children and/or adolescents are affected. Nevertheless, along with the increasing prevalence of childhood obesity, the prevalence of the metabolic syndrome in obese children is reported at 30%, irrespective of the definition applied. Moreover, childhood obesity is associated with sleep-disordered breathing. Adipocytokines, cytokines secreted from adipose tissue, are thought to play a major role in the pathophysiology of metabolic syndrome. Leptin was initially suggested as a promising "anti-obesity" hormone. New concepts indicate that in humans leptin and its soluble receptor may be more important in states of energy deficiency rather than a predictor of the metabolic syndrome. Adiponectin, on the other hand, is not only related to obesity and insulin resistance, but appears to be the strongest predictor for metabolic syndrome, even in children. In newborns and infants, both adipocytokines occur in high concentrations, even though this cannot completely explain the increased risk for ensuing metabolic disease later in life. Finally, low-grade systemic inflammation may underlie the clustering of metabolic risk factors. Overall factors from the adipose tissue may constitute not only markers but also mediators of metabolic sequelae of obesity.

Ocular complications at the limits of viability.

AIM: To evaluate the incidence of retinopathy of prematurity (ROP) and other ocular morbidities in extremely premature infants. METHODS: A retrospective analysis of the prevalence and nature of ocular abnormalities in a cohort of 22 extremely pre-term infants born <25 + 0 weeks of estimated gestational age (GA) was performed. RESULTS: The children were grouped according to the observed disorder: 13 out of 22 (59%) neonates with mild ophthalmologic findings (ROP < or = stage II) [Group 1], 5 out of 22 (23%) infants with ROP stage III or more (Group 2) and 4 out of 22 (18%) neonates with severe ocular morbidity (congenital cataract, microphthalmia, partial optic nerve atrophy and corneal perforation due to an ulcer with lens protrusion), partly combined with ROP > or = stage III (three of four). One child of 22 (5%) needed laser therapy. Out of 22 admitted infants, 20 (91%) were discharged alive. CONCLUSION: The high rate of ocular morbidity besides ROP in extremely pre-term infants is noteworthy. Mechanisms influencing the postnatal development of the eye, especially their relation to the grade of prematurity and neonatological therapeutical strategies, require further investigations.

The effect of maturation and sedation on amplitude-integrated electroencephalogram of the preterm neonate: results of a prospective study.

BACKGROUND AND AIM: Amplitude-integrated electroencephalogram (aEEG) is becoming more common in NICUs for monitoring infants after perinatal asphyxia. We used aEEGs for preterm infants, and analysed the influence of sedation and maturation on their aEEG, focusing on continuous activity. METHODS: Weekly or biweekly aEEGs were performed in preterm infants and evaluated by visual analysis. RESULTS: We analysed 92 aEEGs of 56 preterm infants (gestational age (GA) 24 + 6 to 34 + 0 wk, median 30 + 0 wk). In their first week of life, children with higher GA had a higher percentage of continuous activity: with a GA < or = 28 + 0 wk it was 8.1%, 33.5% with a GA from 28 + 1 to 30 + 0 wk (p=0.02), 85.9% with a GA from 30 + 1 to 32 + 0 wk (p=0.005), and 89.1% with a GA from 32 + 1 to 34 + 0 wk. Continuous activity increased with growing postnatal age. With a GA < or = 28 + 0 wk, it rose from 8.1% (first week) to 55.3% (second week) and reached 96.8% (week 6/7) (p=0.017). With GA from 28 + 1 to 30 + 0 wk, continuous activity was 33.5% (first week) and 86.6% (second week) (p=0.03). CONCLUSION: The aEEG of preterm infants appears to be a good tool for monitoring cerebral activity. Continuous activity seems to indicate maturation in the neonatal brain. Further investigations of aEEGs in preterm infants should be performed.

Morphine-related apnoea in CPAP-treated preterm neonates.

BACKGROUND: Morphine can be used to treat pain in preterm neonates with CPAP because of its analgetic potency; however, it is known to induce apnoea. AIM: To evaluate this risk of apnoea. METHODS: We retrospectively analysed 91 preterm neonates with CPAP who received morphine intravenously. The incidence of apnoea 4 h before and after morphine administration was compared. The data were analysed for three dosage groups (<0.01, 0.01-0.03 and 0.03 mg/kg) and according to the incidence of apnoea before morphine application. RESULTS: In the whole group (gestational age 29.1+/-2.9 wk, morphine dosage 0.017+/-0.01 mg/kg) we did not find differences in apnoea before and after morphine (0.9+/-1.8 vs 1.1+/-1.8 apnoea). The only significant increase in apnoea was seen in the subgroup of patients receiving > 0.03 mg/kg (0.3+/-0.67 vs 1.5+/-2.5 apnoea). Interestingly, we found a significantly delayed increase in apnoea in the fourth hour. CONCLUSION: Morphine in preterm infants with CPAP is not widely accepted practice until further randomized studies evaluate efficacy and safety. Morphine in a low dosage (

Hemodynamics among neonates with hypoxic-ischemic encephalopathy during whole-body hypothermia and passive rewarming.

OBJECTIVE: To assess changes in cardiac performance, with Doppler echocardiography, among newborns with hypoxic-ischemic encephalopathy during mild therapeutic hypothermia and during rewarming. METHODS: For 7 asphyxiated neonates (birth weight: 1840-3850 g; umbilical artery pH: 6.70-6.95) who received mild whole-body hypothermia, the following hemodynamic parameters were determined immediately before rewarming (33 degrees C) and during passive rewarming (35 degrees C and 37 degrees C): heart rate, systolic and diastolic blood pressure, core and peripheral temperatures, left ventricular ejection time, mean velocity of aortic flow, stroke volume, and cardiac output. RESULTS: Heart rate decreased during hypothermia. Bradycardia, with heart rates below 80 beats per minute, did not occur. The median difference between core and peripheral temperatures decreased from 2.0 degrees C (range: 0-6.2 degrees C) during hypothermia to 0.7 degrees C (range: 0.4-1.9 degrees C) at normothermia. Cardiac output was reduced to 67% and stroke volume to 77% of the posthypothermic level. The median heart rate was 129 beats per minute before rewarming and increased to 148 beats per minute during complete rewarming. Before and during passive rewarming, hypotension was not observed. Before, during, and at the end of rewarming, the following parameters increased: mean velocity of aortic flow (median: 44, 55, and 58 cm/second, respectively), stroke volume (median: 1.42, 1.55, and 1.94 mL/kg, respectively), and cardiac output (median: 169, 216, and 254 mL/kg per minute, respectively). Left ventricular ejection time remained unchanged. CONCLUSIONS: Whole-body hypothermia resulted in reduced cardiac output, which reached normal levels at the end of passive rewarming, at normothermia. Physiologic cardiovascular mechanisms seemed to be intact to provide sufficient tissue perfusion, with normal blood lactate levels.

Predictive value of umbilical cord blood bilirubin for postnatal hyperbilirubinaemia.

AIM: The study investigated the predictive value of umbilical cord serum (UCS) bilirubin for the postnatal course of bilirubinaemia in healthy term and near-term newborns. METHODS: Term appropriate-for-gestational-age (AGA; n=1100), small-for-gestational-age (SGA; n=163) and near-term infants (GA 34-36 wk; n=78) were included and separated according to their UCS bilirubin levels, starting from <20 (group 1), 20-<30 (2), 30-40 (3) and >40 (4) micromol/l. The newborns were followed for at least 5 postnatal days, and UCS bilirubin values were correlated with the development of hyperbilirubinaemia and phototherapy (PT) treatment. RESULTS: A clear relation between UCS bilirubin and the development of hyperbilirubinaemia was found in all three patient populations. None of the 75 AGA patients of group 1 developed postnatal bilirubin values above 300 micromol/l, whereas 0.3, 3.4 and 8.6% of the patients in groups 2-4, respectively, did so. The frequency of PT increased from 0% in group 1 up to 9.6% in group 4. For the prediction of further need of PT using a UCS bilirubin cut-off level of 30 micromol/l, we found a sensitivity of 90% and a negative predictive value of 99.1%, indicating that all patients with UCS bilirubin values below 30 micromol/l (443/1100 or 40.2%) were at a very low risk of developing dangerous hyperbilirubinaemia. Similar results were obtained in SGA children with a sensitivity of 94.1% and a negative predictive value of 98.6%. In comparison to term newborns, we generally found higher bilirubin values in preterms. A total of 6.4% of preterm children developed bilirubin values over 300 micromol/l, compared with 3% of term children, and 47.4% of preterms had to be treated with PT. Predicting the need of PT by using a UCS bilirubin cut-off level of 30 micromol/l revealed a sensitivity of 70.3% and a negative predictive value of 65.6%. CONCLUSION: These data suggest that UCS bilirubin is useful in predicting the postnatal bilirubin values in term and near-term newborns. We presume that the use of UCS bilirubin values may help detect infants at low risk for postnatal hyperbilirubinaemia and minimize an unnecessary prolongation of hospitalization.

Unusual presentation of congenital disorder of glycosylation type 1a: congenital persistent thrombocytopenia, hypertrophic cardiomyopathy and hydrops-like aspect due to marked peripheral oedema.

UNLABELLED: Of the congenital disorder of glycosylation (CDG) syndromes, type 1a is the most common. CDG 1a is a multisystem disorder with a wide clinical spectrum. We report on a term newborn with a severe and fatal clinical course of CDG 1a syndrome. Skin fibroblasts showed a reduced activity of phosphomannomutase 2 (PMM2) and mutation analysis revealed a compound heterozygous PMM2gene mutation (F119L/F157S). Presenting features at birth were hypertrophic non-obstructive cardiomyopathy, "orange-peel" skin, inverted nipples and a hydrops-like aspect due to marked peripheral oedema. Suspected hydrops fetalis was not confirmed due to lack of ascites and pleural effusions. Striking clinical problems were therapy-resistant arterial hypertension, recurrent pericardial and pleural effusions and feeding difficulties with failure to thrive. Persistent congenital thrombocytopenia and hyperferritinaemia in the absence of infection were noted. Bone marrow cytology revealed a macrophage activation of unknown aetiology. CONCLUSION: Congenital thrombocytopenia, unspecific macrophage activation and a hydrops-like aspect without a real hydrops fetalis broaden the already wide phenotypic spectrum of congenital disorder of glycosylation syndrome type 1a.

Blood flow parameters of the superior mesenteric artery as an early predictor of intestinal dysmotility in preterm infants.

BACKGROUND: Blood flow parameters in the superior mesenteric artery (SMA) change with vasoconstriction or vasodilatation of the intestinal vascular bed. In cases of severe growth retardation as a result of haemodynamic disturbances, the blood flow changes persist into postnatal life. OBJECTIVE: To assess early changes of Doppler sonographic blood flow parameters in the SMA for prediction of later intestinal motility disturbances in preterm infants and tolerance of enteral feeding during the first week of life. MATERIALS AND METHODS: Doppler sonographic blood flow parameters in the SMA were measured on the first day of life and the following 5 days in 478 neonates with a birth weight below 1,500 g. According to the Doppler results, the neonates were divided into two groups-those with pathological parameters and those with normal blood flow parameters. Correlations between blood flow parameters, the development of intestinal dysmotility and the tolerated amount of enteral feeding were calculated. RESULTS: Pathological blood flow parameters were observed in 148 neonates (group 1) and normal blood flow parameters in 330 neonates (group 2). Intestinal motility disturbance occurred in 125 neonates (83%) of group 1 and 47 neonates (15%) of group 2. Neonates in group 2 tolerated significantly more feed by the fifth day of life than neonates in group 1. Postnatal adaptation did not differ between the two groups, although the majority of neonates with intestinal dysmotility were small for gestational age. The predictive value of blood flow parameters for prediction of intestinal motility revealed high sensitivity and specificity by the first postnatal day, 2 or 3 days before development of clinical signs of intestinal dysmotility. There was a strong negative correlation between pathological pulsatility index on day 1 and the quantity of tolerated enteral feeding on day 5. CONCLUSIONS: Pathological blood flow parameters in the SMA can predict problems of intestinal motility and tolerance of enteral feeding. With the early detection of these problems a prompt start of adequate therapy to avoid complications is possible.