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Summary Background and objective Umbilical venous catheters (UVC) and peripherally inserted central catheters (PICC) are commonly used in preterm infants but have been associated with a number of serious complications. We performed a survey in Austria and Germany to assess the use of UVCs and PICCs in preterm infants with a birth weight Methods Electronic survey of participating centers of the NeoVitaA trial. Main outcome parameter was the reported rates of UVC- and PICC-associated complications (infection, thrombosis, emboli, organ injury, arrhythmia, dislocation, miscellaneous). Results In total, 20 neonatal intensive care units (NICU) providing maximal intensive care in Austria and Germany (level I) were contacted, with a senior neonatologist response rate of 12/20 (60%). The reported rates for UVC with a dwell time of 1–10 days were bacterial infection: 4.2 ± 3.4% (range 0–10%); thrombosis: 7.3 ± 7.1% (0–20%); emboli: 0.9 ± 2.0% (0–5%); organ injury: 1.1 ± 1.9% (0–5%); cardiac arrhythmia: 2.2 ± 2.5% (0–5%); and dislocation: 5.4 ± 8.7% (0–30%); and for PICCs with a dwell time of 1–14 days bacterial infection: 15.0 ± 3.4% (range 2.5–30%); thrombosis; 4.3 ± 3.5% (0–10%); emboli: 0.8 ± 1.6% (0–5%); organ injury: 1.5 ± 2.3% (0–5%); cardiac arrhythmia: 1.5 ± 2.3% (0–5%), and dislocation: 8.5 ± 4.6% (0–30%). Conclusion The catheter-related complication rates reported in this survey differed between UVCs and PICCs and were higher than those reported in the literature. To generate more reliable data on this clinically important issue, we plan to perform a large prospective multicenter randomized controlled trial investigating the non-inferiority of a prolonged UVC dwell time (up to 10 days) against the early change (up to 5 days) to a PICC.

(1) Birth asphyxia is a major cause of delivery room resuscitation. Subsequent organ failure and hypoxic–ischemic encephalopathy (HIE) account for 25% of all early postnatal deaths. The neonatal sequential organ failure assessment (nSOFA) considers platelet count and respiratory and cardiovascular dysfunction in neonates with sepsis. To evaluate whether nSOFA is also a useful predictor for in-hospital mortality in neonates (≥36 + 0 weeks of gestation (GA)) following asphyxia with HIE and therapeutic hypothermia (TH), (2) nSOFA was documented at ≤6 h of life. (3) A total of 65 infants fulfilled inclusion criteria for TH. All but one infant received cardiopulmonary resuscitation and/or respiratory support at birth. nSOFA was lower in survivors (median 0 [IQR 0–2]; n = 56, median GA 39 + 3, female n = 28 (50%)) than in non-survivors (median 10 [4–12], p < 0.001; n = 9, median GA 38 + 6, n = 4 (44.4%)). This was also observed for the respiratory (p < 0.001), cardiovascular (p < 0.001), and hematologic sub-scores (p = 0.003). The odds ratio for mortality was 1.6 [95% CI = 1.2–2.1] per one-point increase in nSOFA. The optimal cut-off value of nSOFA to predict mortality was 3.5 (sensitivity 100.0%, specificity 83.9%). (4) Since early accurate prognosis following asphyxia with HIE and TH is essential to guide decision making, nSOFA (≤6 h of life) offers the possibility of identifying infants at risk of mortality.

(1) Birth asphyxia is the major cause for delivery room resuscitation. Subsequent organ failure and hypoxic-ischemic encephalopathy (HIE) account for 25% of all early postnatal deaths. The neonatal Sequential Organ Failure Assessment (nSOFA) considers platelet count, respiratory and cardiovascular dysfunction in neonates with sepsis. To evaluate whether nSOFA is also a useful predictor for in-hospital mortality in neonates (≥ 36+0 weeks of gestation (GA)) following asphyxia with HIE and therapeutic hypothermia (TH), (2) nSOFA was documented at ≤ 6 hours of life. (3) 65 infants fulfilled inclusion criteria for TH. All but one infant received cardiopulmonary resuscitation and/or respiratory support at birth. nSOFA was lower in survivors (median 0 [IQR 0-2]; n = 56, median GA 39+3, female n = 28 (50%)) than in non-survivors (median 10 [4-12], p < 0.001; n = 9, median GA 38+6, n = 4 (44.4%)). This was also observed for the respiratory (p < 0.001), cardiovascular (p < 0.001), and hematologic sub scores (p = 0.003). The odds ratio for mortality was 1.6 [95% CI = 1.2 – 2.1] per one-point increase in nSOFA. The optimal cut-off value of nSOFA to predict mortality was 3.5 (sensitivity 100.0%, specificity 83.9%). (4) Since early accurate prognosis following asphyxia with HIE and TH is essential to guide end-of-life decisions, nSOFA (≤ 6 hours of life) offers the potential to identify infants at risk of mortality.

BACKGROUND AND OBJECTIVES: BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis. METHODS: Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed. RESULTS: We included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1–29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25–126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers. DISCUSSION: BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

Background and ObjectivesBRAT1encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.MethodsThrough a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants inBRAT1for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.ResultsWe included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1–29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25–126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.DiscussionBRAT1encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition ofBRAT1encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

Umbilical venous catheters (UVC) and peripherally inserted central catheters (PICC) are commonly used in preterm infants but have been associated with a number of serious complications. We performed a survey in Austria and Germany to assess the use of UVCs and PICCs in preterm infants with a birth weight 1250 g and associated rates of catheter-related adverse events.Electronic survey of participating centers of the NeoVitaA trial. Main outcome parameter was the reported rates of UVC- and PICC-associated complications (infection, thrombosis, emboli, organ injury, arrhythmia, dislocation, miscellaneous).In total, 20 neonatal intensive care units (NICU) providing maximal intensive care in Austria and Germany (level I) were contacted, with a senior neonatologist response rate of 12/20 (60%). The reported rates for UVC with a dwell time of 1-10 days were bacterial infection: 4.2 ± 3.4% (range 0-10%); thrombosis: 7.3 ± 7.1% (0-20%); emboli: 0.9 ± 2.0% (0-5%); organ injury: 1.1 ± 1.9% (0-5%); cardiac arrhythmia: 2.2 ± 2.5% (0-5%); and dislocation: 5.4 ± 8.7% (0-30%); and for PICCs with a dwell time of 1-14 days bacterial infection: 15.0 ± 3.4% (range 2.5-30%); thrombosis; 4.3 ± 3.5% (0-10%); emboli: 0.8 ± 1.6% (0-5%); organ injury: 1.5 ± 2.3% (0-5%); cardiac arrhythmia: 1.5 ± 2.3% (0-5%), and dislocation: 8.5 ± 4.6% (0-30%).The catheter-related complication rates reported in this survey differed between UVCs and PICCs and were higher than those reported in the literature. To generate more reliable data on this clinically important issue, we plan to perform a large prospective multicenter randomized controlled trial investigating the non-inferiority of a prolonged UVC dwell time (up to 10 days) against the early change (up to 5 days) to a PICC.HINTERGRUND UND ZIEL: Nabelvenenkatheter („umbilical venous catheters“ [UVC]) und periphere zentrale Venenkatheter (PICC) werden häufig bei Frühgeborenen eingesetzt, sind jedoch mit einer Reihe von schwerwiegenden Komplikationen verbunden. In Österreich und Deutschland wurde eine Umfrage durchgeführt, um die Verwendung von UVC und PICC bei Frühgeborenen mit einem Geburtsgewicht 1250 g und die damit verbundenen Raten von katheterbedingten unerwünschten Ereignissen zu bewerten.Elektronische Befragung der teilnehmenden Zentren der NeoVitaA-Studie. Hauptergebnisparameter waren die gemeldeten Raten von UVC- und PICC-assoziierten Komplikationen (Infektion, Thrombose, Embolie, Organverletzung, Arrhythmie, Dislokation, Sonstiges).Insgesamt wurden 20 neonatale Intensivstationen (NICU) mit maximaler Intensivpflege in Österreich und Deutschland (Level I) kontaktiert, wobei 12/20 (60 %) von leitenden Neonatologen beantwortet wurden. Die gemeldeten Raten für UVC mit einer Verweildauer von 1 bis 10 Tagen waren bakterielle Infektionen: 4,2 ± 3,4 % (Bereich: 0–10 %); Thrombose: 7,3 ± 7,1 % (0–20 %); Embolie: 0,9 ± 2,0 % (0–5 %); Organverletzung: 1,1 ± 1,9 % (0–5 %); Herzrhythmusstörungen: 2,2 ± 2,5 % (0–5 %); und Dislokation: 5,4 ± 8,7% (0–30 %); und bei PICC mit einer Verweildauer von 1 bis 14 Tagen bakterielle Infektionen: 15,0 ± 3,4 % (Bereich: 2,5–30 %); Thrombose: 4,3 ± 3,5 % (0–10 %); Embolie: 0,8 ± 1,6 % (0–5 %); Organverletzung: 1,5 ± 2,3 % (0–5 %); Herzrhythmusstörungen: 1,5 ± 2,3 % (0–5 %) und Verrenkungen: 8,5 ± 4,6 % (0–30 %).Die in dieser Umfrage berichteten katheterbedingten Komplikationsraten unterschieden sich zwischen UVC und PICC und waren höher als die in der Literatur berichteten. Um zuverlässigere Daten zu diesem klinisch wichtigen Thema zu erhalten, ist eine große prospektive, multizentrische, randomisierte, kontrollierte Studie geplant, in der die Nichtunterlegenheit einer verlängerten UVC-Verweildauer (bis zu 10 Tage) gegenüber dem frühen Wechsel (bis zu 5 Tage) zu einem PICC untersucht werden soll.

Background and Purpose: Associations of APOE genotypes with intracerebral hemorrhage (ICH) in preterm infants were previously described. In adults, APOE-ε4 genotype has been proposed as susceptibility factor for impaired recovery after cerebral insult. We here aim to determine APOE genotype-specific neurological consequences of neonatal ICH at school age. Methods: In this multicenter observational cohort study, very low birth weight ( Results: Two thousand two hundred fifteen children participated at follow-up, including 363 children with ultrasound diagnosed neonatal ICH. In univariate analyses of children with a history of ICH, APOE-ε3 carriers had lower frequencies of CP (n=33/250; 13.2 [95% CI, 9.4%–17.8%]), as compared to APOE-ε2 (n=15/63; 23.8 [14.6%–35.3%], P =0.037) and –ε4 carriers (n=31/107; 29.0 [21.0%–38.0%], P P =0.002) after ICH. Notably, at low-grade ICH (grade I) APOE-ε4 expression resulted in an increased rate of CP (n=6/39; 15.4 [6.7–29.0]) in comparison to APOE-ε3 (n=2/105; 1.9 [0.4%–6.0%], P =0.002). Conclusions: APOE-ε4 carriers have an increased risk for long-term motor deficits after ICH. We assume an effect even after low-grade neonatal ICH, but more data are needed to clarify this issue.

Therapeutic hypothermia (TH) for 72 h is the standard treatment to reduce neurological deficits in term newborns with hypoxic-ischemic encephalopathy. There is a large variability regarding nutritional supply during TH treatment in asphyxiated newborns. We performed a retrospective multicentre study in four level I (highest level of care in Germany) NICUs, including 135 asphyxiated term newborns undergoing TH. We analyzed enteral and parenteral nutritional supply during and after TH. We correlated nutritional supply with risk factors for encephalopathy, pH, Sarnat score, mechanical ventilation, seizures, and sedation. A total of 120 of 135 neonates received enteral nutritional supply within the first 24 h, and the majority of children were fully enterally fed within the first 10 days. The grade of encephalopathy and mechanical ventilation had a significant influence on the amount of enteral fluids (p = 0.01), whereas the pH and appearance of seizures did not affect the amount of nutritional supply significantly. Furthermore, we did not observe any correlation between enteral intake and abdominal complications such as necrotizing enterocolitis. We observed a large variability of feeding regimes in the four participating NICUs. Early enteral feeding among newborns undergoing TH was performed in each NICU and was well tolerated without increased rates of complications.

Neonates treated with therapeutic hypothermia (TH) following perinatal asphyxia (PA) suffer a considerable rate of disability and mortality. Several risk factors associated with adverse outcomes have been identified. Mechanical ventilation might increase the risk for hyperoxia and hypocapnia in cooled newborns. We carried out a retrospective study in 71 asphyxiated cooled newborns. We analyzed the association of ventilation status and adverse short-term outcomes and investigated the effect of the former on pCO2 and oxygen delivery before, during and after TH. Death, abnormal findings on magnetic resonance imaging, and pathological amplitude-integrated electroencephalography traces were used to define short-term outcomes. The need for mechanical ventilation was significantly higher in the newborns with adverse outcomes (38% vs. 5.6%, p = 0.001). Compared to spontaneously breathing neonates, intubated newborns suffered from significantly more severe asphyxia, had significantly lower levels of mean minimum pCO2 over the first 6 and 72 h of life (HOL) (p = 0.03 and p = 0.01, respectively) and increased supply of inspired oxygen, which was, in turn, significantly higher in the newborns with adverse outcomes (p &lt, 0.01). Intubated newborns with adverse short-term outcomes had lower levels of pCO2 over the first 36 HOL. In conclusion, need for mechanical ventilation was significantly higher in newborns with more severe asphyxia. In ventilated newborns, level of encephalopathy, lower pCO2 levels, and increased oxygen supplementation were significantly higher in the adverse short-term outcomes group. Ventilatory parameters need to be carefully monitored in cooled asphyxiated newborns.

MFSD2A, a member of the major facilitator superfamily (MFS), is a transmembrane transporter responsible for the uptake of specific essential fatty acids through the blood-brain barrier (BBB) to the brain. The transporter is crucial for early embryonic brain development and a major factor in the formation and maintenance of the BBB. Mfsd2a-knockout mice show a leakage of the BBB in early embryonic stages and develop a phenotype characterized by microcephaly, cognitive impairment, and anxiety. So far, homozygous or compound heterozygous MFSD2A mutations in humans have only been reported in 13 different families with a total of 28 affected individuals. The phenotypical spectrum of patients with MFSD2A variants is rather broad but all patients present with microcephaly and severe intellectual disability, absent or limited speech, and walking difficulties. Severely affected patients develop seizures and show brain malformations and have, above all, a profound developmental delay hardly reaching any developmental motor milestones. Here, we report on two unrelated individuals with novel homozygous variants in the MFSD2A gene, presenting with severe primary microcephaly, brain malformations, profound developmental delay, and epilepsy, including hypsarrhythmia. Our findings extend the mutational spectrum of the bi-allelic MFSD2A variants causing autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants emphasizing the role of MFSD2A in early brain development.

Objective: To evaluate the nutrition-related effects of prophylactic Lactobacillus acidophilus/Bifidobacterium infantis probiotics on the outcomes of preterm infants &lt, 29 weeks of gestation that receive human milk and/or formula nutrition. We hypothesize that human-milk-fed infants benefit from probiotics in terms of sepsis prevention and growth. Methods: We performed an observational study of the German Neonatal Network (GNN) over a period of six years, between 1 January, 2013 and 31 December, 2018. Prophylactic probiotic use of L. acidophilus/B. infantis was evaluated in preterm infants &lt, 29 weeks of gestation (n = 7516) in subgroups stratified to feeding type: (I) Exclusively human milk (HM) of own mother and/or donors (HM group, n = 1568), (II) HM of own mother and/or donor and formula (Mix group, n = 5221), and (III) exclusive exposure to formula (F group, n = 727). The effect of probiotics on general outcomes and growth was tested in univariate models and adjusted in linear/logistic regression models. Results: 5954 (76.5%) infants received L. acidophilus/B. infantis prophylactically for the prevention of necrotizing enterocolitis (NEC). Probiotic use was associated with improved growth measures in the HM group (e.g., weight gain velocity in g/day: effect size B = 0.224, 95% CI: 2.82&ndash, 4.35, p &lt, 0.001) but not in the F group (effect size B = &minus, 0.06, 95% CI: &minus, 3.05&ndash, 0.28, p = 0.103). The HM group had the lowest incidence of clinical sepsis (34.0%) as compared to the Mix group (35.5%) and the F group (40.0%). Only in the Mix group, probiotic supplementation proved to be protective against clinical sepsis (OR 0.69, 95% CI: 0.59&ndash, 0.79, 0.001). Conclusion: Our observational data indicate that the exposure to L. acidophilus/B. infantis probiotics may promote growth in exclusively HM-fed infants as compared to formula-fed infants. To exert a sepsis-preventive effect, probiotics seem to require human milk.

Background Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. Bi-allelic pathogenic variants in POMK are the cause of a broad spectrum of alpha-dystroglycanopathies. POMK encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition. Results Here, we report on male monozygotic twins with severe CNS malformations (hydrocephalus, cortical malformation, hypoplastic cerebellum, and most prominently occipital meningocele), eye malformations and highly elevated creatine kinase, indicating the clinical diagnosis of a congenital muscular dystrophy (alpha-dystroglycanopathy). Both twins were found to harbor a homozygous nonsense mutation c.640C>T, p.214* in POMK, confirming the clinical diagnosis and supporting the concept that POMK mutations can be causative of WWS. Conclusion Our combined data suggest a more important role for POMK in the pathogenesis of meningoencephalocele. Only eight different pathogenic POMK variants have been published so far, detected in eight families; only five showed the severe WWS phenotype, suggesting that POMK-associated WWS is an extremely rare disease. We expand the phenotypic and mutational spectrum of POMK-associated WWS and provide evidence of the broad phenotypic variability of POMK-associated disease.

Background Vancomycin is an extensively used anti-infective drug in neonatal ICUs. However, exposure–toxicity relationships have not been clearly defined. Objectives To evaluate the risk profile for hearing deficits in vancomycin-exposed very-low-birthweight infants (VLBWI). Methods In a large cohort study of the German Neonatal Network (GNN; n = 16 967 VLBWI) we assessed the association of vancomycin treatment and pathological hearing tests at discharge and at 5 year follow-up. We performed audits on vancomycin exposure, drug levels, dose adjustments and exposure to other ototoxic drugs in a subgroup of 1042 vancomycin-treated VLBWI. Results In the GNN cohort, 28% (n = 4739) were exposed to IV vancomycin therapy. In multivariable logistic regression analysis, vancomycin exposure proved to be independently associated with pathological hearing test at discharge (OR 1.18, 95% CI 1.03–1.34, P = 0.016). Among vancomycin-treated infants, a cumulative vancomycin dose above the upper quartile (>314 mg/kg bodyweight) was associated with pathological hearing test at discharge (OR 2.1, 95% CI 1.21–3.64, P = 0.009), whereas a vancomycin cumulative dose below the upper quartile was associated with a reduced risk of pathological tone audiometry results at 5 years of age (OR 0.29, 95% CI 0.1–0.8, P = 0.02, n = 147). Conclusions Vancomycin exposure in VLBWI is associated with an increased, dose-dependent risk of pathological hearing test results at discharge and at 5 years of age. Prospective studies on long-term hearing impairment are needed.

BACKGROUND NOD2 loss-of-function mutations, that is, R702W [rs2066844], G908R [rs2066845], and Leu1007fsinsC [rs5743293], have been linked to inflammatory bowel diseases. It is yet unknown whether these variants are also associated with necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) in infants of very low birth weight (VLBW). METHODS To test this hypothesis, we genotyped 9082 VLBW infants with European ancestry enrolled in a prospective, population-based cohort study of the German Neonatal Network. We assessed the effect of the NOD2 gene variants on the risk for major morbidities of the gastrointestinal tract, that is, NEC/FIP requiring surgery in multivariable logistic regression analyses. RESULTS In the whole cohort of VLBW infants, carriers of ≥ 2 NOD2 variant alleles had an increased risk for NEC requiring surgery (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.27-10.04; P = 0.03) and NEC or FIP requiring surgery (OR, 3.81; 95% CI, 1.70-8.51; P = 0.004) as compared with wild-type genotypes. In a multivariable logistic regression analysis including gestational age, birth weight, gender, multiple birth, and inborn delivery, the association between ≥ 2 NOD2 variant alleles and NEC surgery (OR, 4.14; 95% CI, 1.41-12.12; P = 0.009), FIP surgery (OR, 3.50; 95% CI, 1.02-12.04; P = 0.047), and NEC or FIP surgery (OR, 4.10; 95% CI, 1.74-9.73; P = 0.001) proved to be independent. We also performed a regression analysis in the subgroup of infants with available information on Lactobacillus acidophilus/Bifidobacterium infantis probiotic supplementation (n = 3638). Although probiotics had a protective effect on NEC and NEC or FIP requiring surgery, the NOD2 variants had no significant impact in this subgroup. CONCLUSIONS VLBW infants carrying ≥ 2 NOD2 genetic risk factors of inflammatory bowel disease in adults have an increased risk for severe gastrointestinal complications, such as NEC requiring surgery. Therefore, infants might benefit from NOD2 genotyping followed by supplementation with probiotics. Replication studies are needed along with genome-wide arrays to allow risk-adapted prevention and therapeutic strategies.

Aim Infants born preterm are at risk of intraventricular haemorrhage (IVH) but individual susceptibility related to genes is not well defined in this vulnerable population. Apolipoprotein genotypes APOE2 and APOE4 increase the hazard of cerebral haemorrhages in adults. We investigated whether APOE is associated with prevalence of IVH and is likely to have a particular genotype. Method In this prospective study, 5075 infants born preterm with genotype APOE3 were compared to 965 (APOE2) and 1912 (APOE4) individuals, to analyse the association between APOE genotype and grade III and IV IVH. We used a logistic regression model including gestational age, antenatal steroid treatment, 5-minute Apgar scores less than 3, intubation, pneumothorax, small for gestational age, multiple birth, sex, and maternal descent as independent factors. Results The APOE2 (20.1%) and APOE4 (19.8%) genotypes were significantly more prevalent in infants with IVH than in those with the APOE3 haplotype (17.4%) (APOE2: odds ratio [OR] 1.33, 95% confidence interval [CI] 1.00-1.76; APOE4: OR 1.39, 95% CI 1.12-1.74). Infants with two polymorphisms had the highest risk of IVH (8.7%; OR 1.63, 95% CI 1.09-2.45). Interpretation APOE2 and APOE4 genotypes are relevant risk factors for IVH in infants born preterm. Our findings improve our understanding of the genetic contributions to IVH.

Wir berichten von einem Fruhgeborenen [Gestationsalter 24 5/7 Schwangerschaftswochen (SSW)], das am 11. Lebenstag eine schwere Sepsis mit Escherichia-coli-Pneumonie entwickelte. 9 Wochen nach Diagnosestellung wurden Verkalkungen des Lungenparenchyms rechts festgestellt. Nach intermittierender antibiotischer Therapie fur insgesamt 98 Tage, 47 Tagen invasiver Beatmung und 65 Tagen CPAP-Atemunterstutzung (CPAP: „continuous positive airway pressure“) wurde die Patientin mit zusatzlichem Sauerstoffbedarf entlassen.

BACKGROUND:Experimental studies suggest that platelet-triggered ductal sealing is critically involved in definite ductus arteriosus closure. Whether thrombocytopenia contributes to persistently patent ductus arteriosus (PDA) in humans is controversial. This was a retrospective study of 1350 very low birth weight (VLBW; METHODS:All infants who had a platelet count in the first 24 hours after birth and an echocardiogram performed on day of life 4 to 5 were included. The incidence of thrombocytopenia was analyzed in infants with and without PDA, and in those who did or did not undergo PDA intervention. The impact of thrombocytopenia, gestational age, birth weight, gender, and sepsis on PDA was determined by receiver operating characteristic curve, odds ratio, and regression analyses.RESULTS:Platelet numbers within the first 24 hours after birth did not differ between VLBW/ELBW infants with and without spontaneous ductal closure. Platelet numbers were not associated with subsequent PDA treatment. Low platelet counts were not related to failure of pharma-cologic PDA treatment and the need for subsequent surgical ligation. Lower gestational age or birth weight, male gender, and sepsis were linked to the presence of PDA in VLBW infants on day of life 4 to 5.CONCLUSIONS:Thrombocytopenia in the first 24 hours after birth was not associated with PDA in this largest VLBW/ELBW infant cohort studied to date. Impaired platelet function, due to immaturity and critical illness, rather than platelet number, might play a role in ductus arteriosus patency.

Treacher Collins syndrome (TCS) is the most common and well-known mandibulofacial dysostosis caused by mutations in at least three genes involved in pre-rRNA transcription, the TCOF1, POLR1D and POLR1C genes. We present a severely affected male individual with TCS with a heterozygous de novo frameshift mutation within the TCOF1 gene (c.790_791delAG,p.Ser264GlnfsX7) and compare the clinical findings with three previously unpublished, milder affected individuals from two families with the same mutation. We elucidate typical clinical features of TCS and its clinical implications for the paediatrician and mandibulofacial surgeon, especially in severely affected individuals and give a short review of the literature. Conclusion:The clinical data of these three families illustrate that the phenotype associated with this specific mutation has a wide intra- and interfamilial variability, which confirms that variable expressivity in carriers of TCOF1 mutations is not a simple consequence of the mutation but might be modified by the combination of genetic, environmental and stochastic factors. Being such a highly complex disease treatment of individuals with TCS should be tailored to the specific needs of each individual, preferably by a multidisciplinary team consisting of paediatricians, craniofacial surgeons and geneticists.

6 cases of clinical influenza A/H1N1(2009) infections were reported within the multi-center German Neonatal Network (GNN) during the primary hospital stay in the pandemic season 2009/2010 and 2010/2011. Clinical symptoms varied from transient hyperthermia to apnea and severe respiratory distress. 1 fatal course with systemic inflammatory response after perinatal transmission of A/H1N1(2009) was observed. Oseltamivir treatment in 3/6 infants was without side effects. The reported cases have major implications for the management of VLBW infants: i) fatal courses after perinatal transmission are possible, ii) postnatal A/H1N1(2009) infection may result in life threatening events at a time when the infant is otherwise stable, iii) vaccination should be recommended for parents and medical staff to avoid nosocomial transmission, iv) more data are needed on the benefit and harm of antiviral drugs in preterm infants, v) neonatologists should suspect A/H1N1(2009) infection when unexplained sepsis-like or respiratory symptoms occur in VLBW infants.

Introduction In the German Neonatal Network (GNN) 10% of very-low-birth weight infants (VLBWI) suffer from blood-culture confirmed sepsis, while 30% of VLBWI develop clinical sepsis. Diagnosis of sepsis is a difficult task leading to potential over-treatment with antibiotics. This study aims to investigate whether the results of blood multiplex-PCR (SeptiFast®) for common sepsis pathogens are relevant for clinical decision making when sepsis is suspected in VLBWI. Methods We performed a prospective, multi-centre study within the GNN including 133 VLBWI with 214 episodes of suspected late onset sepsis (LOS). In patients with suspected sepsis a multiplex-PCR (LightCycler SeptiFast MGRADE-test®) was performed from 100 μl EDTA blood in addition to center-specific laboratory biomarkers. The attending neonatologist documented whether the PCR-result, which was available after 24 to 48 hrs, had an impact on the choice of antibiotic drugs and duration of therapy. Results PCR was positive in 110/214 episodes (51%) and blood culture (BC) was positive in 55 episodes (26%). Both methods yielded predominantly coagulase-negative staphylococci (CoNS) followed by Escherichia coli and Staphylococcus aureus. In 214 BC—PCR paired samples concordant results were documented in 126 episodes (59%; n = 32 were concordant pathogen positive results, n = 94 were negative in both methods). In 65 episodes (30%) we found positive PCR results but negative BCs, with CoNS being identified in 43 (66%) of these samples. Multiplex-PCR results influenced clinical decision making in 30% of episodes, specifically in 18% for the choice of antimicrobial therapy and in 22% for the duration of antimicrobial therapy. Conclusions Multiplex-PCR results had a moderate impact on clinical management in about one third of LOS-episodes. The main advantage of multiplex-PCR was the rapid detection of pathogens from micro-volume blood samples. In VLBWI limitations include risk of contamination, lack of resistance testing and high costs. The high rate of positive PCR results in episodes of negative BC might lead to overtreatment of infants which is associated with risk of mortality, antibiotic resistance, fungal sepsis and NEC.

Background: In very low birth weight (VLBW) infants, obstructive bronchitis is a frequent cause of hospital re-admission. For VLBW infants, early vaccinations starting at 2 months after birth have been recommended. Objective: To analyze risk factors for bronchitis during the first year after discharge and the effects of in-hospital standard vaccination (hexavalent/pneumococci) and/or RSV immunoprophylaxis with palivizumab. Methods: A standardized questionnaire was sent to the parents of VLBW infants 7 month after discharge. The reported episodes of bronchitis were correlated with clinically recorded parameters including risk factors for pulmonary morbidity. The effects of in-hospital vaccination were assessed in a subgroup discharged after day 60. Results: A sample of 1 967 responses of infants born 2009–2011 was analyzed. Risk factors for bronchitis were male gender and older siblings. 24% of the population had episodes of bronchitis. In the subgroup discharged after day 60, episodes of bronchitis were reported for 31% of infants who were not vaccinated in-hospital. A significant reduction of the bronchitis rate was found in infants who received palivizumab±standard vaccination (17% bronchitis, p=0.003). Interestingly, in-hospital standard vaccination without RSV immunoprophylaxis was protective (20% bronchitis; p=0.037) as well. Conclusions: Non-vaccinated male VLBW infants with older siblings are at increased risk for bronchitis during the first year after discharge. Vaccination according to schedule seems to have protective effects, while underlying mechanisms are unknown. The rate of timely vaccination in preterm infants should be increased.

Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.

Several studies have revealed the importance of brain imaging in term and preterm infants. The aim of this retrospective study was to review safety, handling, and image quality of MR brain imaging using a new 3 Tesla MR-compatible incubator. Between 02/2011 and 05/2012 100 brain MRIs (84 infants, mean gestational age 32.2 ± 4.7 weeks, mean postmenstrual age at imaging 40.6 ± 3.4 weeks) were performed using a 3 Tesla MR-compatible incubator with dedicated, compatible head coil. Seventeen examinations (13 infants, mean gestational age 35.1 ± 5.4 weeks, mean postmenstrual age at imaging 47.8 ± 7.4 weeks) with a standard head coil served as a control. Image analysis was performed by a neuroradiologist and a pediatric radiologist in consensus. All but two patients with known apnea were transferred to the MR unit and scanned without problems. Handling was easier and faster with the incubator; relevant motion artifacts (5.9 vs. 10.8 %) and the need for repetitive sedation (43.0 vs. 86.7 %) were reduced. Considering only images not impaired by motion artifacts, image quality (4.8 ± 0.4 vs. 4.3 ± 0.8, p = 0.047) and spatial resolution (4.7 ± 0.4 vs. 4.2 ± 0.6, p = 0.011) of T2-weighted images were scored significantly higher in patients imaged with the incubator. SNR increased significantly (171.6 ± 54.5 vs. 80.5 ± 19.8, p

Background Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown. Methods We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients. Results Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression. Conclusions This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFβ1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD. © 2012, International & American Associations for Dental Research. All rights reserved.

The German Neonatal Network (GNN) is a prospective cohort study with the focus on long term development of very-low-birth-weight infants. It was the aim of this study to determine detailed information on causes of mortality in the GNN birth cohort 2010.Major contributors to hospital mortality were recorded by the attending neonatologists for the cohort of very-low-birth-weight (VLBW) infants born in centres of the German Neonatal Network (GNN) in 2010. The data quality was approved by on-site monitoring.2 221 VLBW infants were born in GNN centres in 2010, and death occurred in 221 infants. Male infants carried a higher risk than females (58.8% males among non-survivors vs. 51.7% among survivors, p=0.047). In 11 infants, the major contributor to death was not determined by the attending neonatologist. In 25 infants born at the limit of viability, comfort palliative care was primarily initiated and 14 infants had lethal malformations. The majority of non-survivors suffered from inflammatory diseases including sepsis- or necrotizing enterocolitis (NEC)-associated death (n=56). Respiratory pathology was a major contributor to death in 65 infants including 11 infants who died from pulmonary haemorrhage.Potentially preventable complications of preterm birth such as sepsis, NEC and pulmonary haemorrhage predominate the major contributors to mortality in the GNN 2010 cohort. In order to decrease the rate of these associated deaths, future trials should focus on prophylaxis and therapy optimization strategies for these outcomes.