Impact of early antibiotic exposure on the risk of colonization with potential pathogens in very preterm infants: a retrospective cohort analysis.

BACKGROUND: Sepsis is one of the most important complications in preterm infants. For this reason, most preterm infants receive antibiotics during their first postnatal week. Since 2013, a weekly colonization screening has been installed in German neonatal intensive care units (NICUs), including multi-drug resistant organisms (MDRO) and pathogens with increased epidemic potential. We here investigated the impact of early antibiotic exposure on the colonization with these pathogens. METHODS: Data from 1407 preterm infants with gestational age < 32 + 0 weeks and born in three NICUs in Germany between January 2014 and December 2019 were analysed. RESULTS: Antibiotics were administered to 911/1407 (64.7%) participating infants during their first postnatal week. Screening-targeted pathogens were detected in 547/1407 (38.9%). Early antibiotic exposure did not increase the risk of colonization with screening-targeted pathogens. The only independent risk factor for colonisation with potential pathogens was the admitting hospital. Interestingly, longer antibiotic therapy (> 7 days) decreased the risk for acquiring pathogens with increased epidemic potential. CONCLUSION: Early antibiotic exposure did not impact the risk for colonization with MDRO or highly epidemic pathogens in preterm infants. Further studies are needed to identify risk factors for the acquisition of MDRO and highly epidemic pathogens and potential associations with long-term outcome.

Evidence and practical aspects of treatment with the Tübingen palatal plate.

The Tübingen therapy concept centers on an individual orthodontic palatal plate with a spur-like velar extension (Tübingen Palatal or Epiglottic Baton Plate, TPP or PEBP) and intensive feeding training. It was primarily developed for infants with Robin sequence, but has since also be used successfully in infants with other craniofacial malformations. TPP improves not only upper airway obstruction, but also feeding problems, thriving, mandibular growth and was associated with intact neurocognitive outcome. This review provides an overview of the evidence and the clinical and practical aspects of the Tübingen therapy concept.

Retrospective study on growth in infants with isolated Robin sequence treated with the Tuebingen Palate Plate.

BACKGROUND: Children with Robin sequence (RS) are at risk of growth failure, mainly due to their increased work of breathing and feeding difficulties. Various conservative and surgical treatment approaches exist, but their impact on weight gain has not yet been adequately addressed. A functional treatment concept, used in our center for > 20 years, includes a pre-epiglottic baton plate (Tuebingen palatal plate) and intensive feeding training. OBJECTIVE: To investigate the effect of the Tuebingen treatment protocol on growth and weight trajectories during infancy. METHODS: This retrospective study analyzed longitudinal data from infants with isolated RS admitted to Tuebingen University Children's Hospital, Germany between 1998 and 2019. Through our electronic patient database, we evaluated anthropometric parameters until reaching 1-year follow-up. Results are shown as median (IQR). RESULTS: In 307 infants analyzed, median Z-score for weight decreased from - 0.28 at birth to - 1.12 upon admission to our center at a median age of 22 days. Z-score then remained largely unchanged until discharge (Z-score difference, - 0.08), while the proportion of infants receiving tube feedings decreased from 55.1 to 13.7%. Z-score subsequently increased from - 1.17 at discharge to - 0.44 at the 1-year follow-up (p < 0.001). CONCLUSION: Based on a comparatively large cohort, this functional treatment was associated with better weight gain and improved feeding. As RS infants often show postnatal growth failure, weight monitoring may be a valuable parameter for monitoring treatment effectiveness. Clinical Trial Registration Not necessary due to the retrospective design.

In vitro evaluation of delays in the adjustment of the fraction of inspired oxygen during CPAP: effect of flow and volume.

BACKGROUND: Adjusting the fraction of inspired oxygen (FiO2) delivered to preterm infants to keep their oxygen saturation within target range remains challenging. Closed-loop automated FiO2 control increases the time infants spend within the assigned target range. The delay with which FiO2 adjustments at the ventilator result in a change in the inspired gas limits the performance of both manual and automated controls. OBJECTIVE: To evaluate the equilibration time (Teq) between FiO2 adjustments and changes in FiO2 reaching the patient. METHODS: In vitro determination of the delay in FiO2 adjustments at the ventilator at 5 and 8 L/min of gas flow and two different humidifier/ventilator circuit volumes (840 and 432 mL). RESULTS: Teq values were 31, 23, 20 and 17 s for the volume-flow combinations 840 mL+5 L/min, 840 mL+8 L/min, 432 mL+5 L/min and 432 mL+8 L/min, respectively. CONCLUSION: The identified delay seems clinically relevant and should be taken into account during manual and automatic control of FiO2.

Granulocytic Myeloid-Derived Suppressor Cells in Breast Milk (BM-MDSC) Correlate with Gestational Age and Postnatal Age and Are Influenced by Infant's Sex.

BACKGROUND: Infections are the main cause of death in preterm infants. Causative agents often descend from the intestinal flora of the infected neonate, indicating insufficient protection by the mucosal barrier. Breast milk (BM) contains different subsets of immune cells. We recently showed that BM contains significant numbers of myeloid-derived suppressor cells (MDSC)-immune cells that actively suppress pro-inflammatory immune responses-and hypothesized that the transfer of BM-MDSC may modulate the mucosal immunity of the newborn. METHODS: Percentages of MDSC in the BM from mothers of 86 preterm infants between 23 + 0 and 36 + 6 weeks of gestation during their first five postnatal weeks were analyzed by flow cytometry and correlated with maternal and infant characteristics. RESULTS: Percentages of BM-MDSC positively correlated with gestational age and postnatal age. The expression of activation markers on BM-MDSC did not change with gestational age, but it decreased with postnatal age. Mothers who received antepartum tocolytics had lower percentages of BM-MDSC, and infant's sex strongly influenced percentages of BM-MDSC. CONCLUSION: Our results point toward a role of BM-MDSC for immune regulation in the neonatal gut, making them a potential target of immune-based therapies shortly after birth.

An innovative method for manufacturing the Tuebingen palatal plate for infants with Robin sequence.

BACKGROUND: Robin sequence (RS) is characterized by mandibular micro- and retrognathia, glossoptosis, upper airway obstruction and optionally a cleft palate. With an incidence of 1:8000, it belongs to the so-called rare diseases; 30-50% of patients have RS as part of a syndrome. A comparatively well-studied treatment option is the Tuebingen Palatal Plate (TPP), which has proven effective in both, isolated and syndromic RS, but often requires multiple endoscopies for perfect fit and effectiveness. We report on a new method for fitting the TPP with only one session of nasopharyngeal endoscopy resulting in the plate being finished in one day. METHODS AND RESULTS: First, a prototype is produced, consisting of a traditional acrylic palatal part and a velar extension made of thermoplastic resin, usually measuring 10x40mm. Using polymerization, a scale is added to the posterior part of the extension to help with determining its optimal length during endoscopic evaluation. The extension is pre-bent in the dental laboratory to achieve an approximate shape. During endoscopy, the prototype can be adjusted to the infant's anatomy: first, the angulation is customized by controlled heating, bending and cooling of the thermoplastic spur. Second, the length of the spur is adapted by grinding its tip. Then the prototype is returned to the dental laboratory for completion; the final plate can be delivered to the patient on the same day. It acts by shifting the tongue into a more anterior position, thereby opening the airway and releasing upper airway obstruction, as well as by acting as a functional orthodontic appliance that stimulates mandibular growth through exerting pressure on the base of the tongue. CONCLUSIONS: With the thermoplastic spur presented here, a TPP can be produced within one day, requiring only one endoscopy. This approach may facilitate fabricating the TPP.

Mandibular growth in infants with Robin sequence treated with the Tübingen palatal plate.

BACKGROUND: Robin sequence (RS) is characterized by mandibular retrognathia, glossoptosis and upper airway obstruction. Whether mandibular catch-up growth may occur in RS is yet controversial. Our functional and less invasive treatment including the Tübingen Palatal Plate (TPP), early oral feeding and orofacial stimulation may promote mandibular catch-up growth. We evaluated the effect of the Tübingen Palatal Plate on mandibular growth, expressed by the Jaw index, sleep study results and weight gain in infants admitted with isolated and syndromic RS, born at or referred to our center between 6/2015 and 5/2018. METHODS: Retrospective analysis of our electronic patient database that included data on jaw index measurements, sleep study results and standard deviation (Z-)scores for weight. RESULTS: Of 31 patients referred for RS treatment (22 isolated, 9 syndromic), we had data on the above parameters, determined at admission, discharge and 3 months after discharge, in 20. Jaw index at admission and 3-month follow-up was 8.8 (6.3-11.3) and 2.1 (2.0-4.0), respectively (median (IQR); p < 0.0001). Mixed-obstructive apnea index (MOAI) decreased from 9.7 (4.8-24.2) to 0.0 (0-1.3; p < 0.002). No significant correlation was observed between MOAI and Jaw Index, but MOAI correlated with the Maxillary/Mandibular arch ratio (r = 0.58; p < 0.001). Z-scores for weight were similar at both time points at - 1.34 (- 1.76 - - 0.57) and - 1.50 (- 1.89 - - 0.54), while the proportion of infants requiring nasogastric tube feeding decreased from 84 to 8%. No infant had craniofacial surgery; one with syndromic RS required tracheostomy. CONCLUSION: These longitudinal cohort data suggest that the Tübingen Palatal Plate as used here may alleviate upper airway obstruction by promoting mandibular growth. TRIAL REGISTRATION: N.A.

Less invasive treatment of sleep-disordered breathing in children with syndromic craniosynostosis.

BACKGROUND: Infants and children with syndromic craniosynostosis (SCS), such as Apert-, Crouzon- or Pfeiffer syndrome, are prone to sleep disordered breathing (SDB) including obstructive sleep apnea and upper airway resistance syndrome (OSAS, UARS), potentially leading to tracheostomy. We modified the Tübingen Palatal Plate (TPP), an oral appliance with a velar extension effectively treating airway obstruction in Robin sequence, by attaching a tube to its velar extension to bridge the narrow pharyngeal airway in SCS patients. Here, we evaluated this treatment concept. METHODS: Our hospital's electronic patient files were searched for all children with a diagnosis of SCS admitted between 01/01/2004 and 31/12/2016. Children with isolated craniosynostosis were excluded. OSAS was defined as a mixed-obstructive apnea-hypopnea index (MOAHI) > 1, and UARS as more than 1 episode with nasal flow limitation/h, but absent OSAS. Children with a diagnosis of OSAS received the TPP and fiberoptic nasopharyngoscopy to assess the type of obstruction and to adjust the plate. Growth and weight gain, determined as standard deviation scores, were also evaluated before and during treatment. RESULTS: Of 34 patients included, 24 presented with SDB (19 OSAS, 5 UARS) and 27 had midface hypoplasia. Proportions of SDB were 78% in those with, and 22% in those without midface hypoplasia. In the OSAS group (n = 19), 13 patients were treated with palatal plates, with the remaining receiving continuous positive airway pressure, midface surgery or tracheal intubation. The MOAHI decreased across all children receiving palatal plate treatment from 14.6 (range 0.0-50.7) at admission to 0.9 (range 0.0-3.5) at discharge (p = 0.002). SDS for weight and body length also improved (p < 0.05 for weight and p = 0.05 for body length). Only one child required tracheostomy. CONCLUSION: Treatment of upper airway obstruction by a modified TPP in these children with SCS was shown to be mostly effective and safe. If confirmed in larger prospective studies, it may help to avoid more invasive interventions.

Growth and morbidity of extremely preterm infants after early full enteral nutrition.

OBJECTIVES: To evaluate feasibility and consequences of accelerated feeding advancement on short-term outcomes in extremely low gestational age neonates (ELGANs) who stayed in our institution for >28 days. METHODS: Retrospective single-centre cohort analysis covering the years 2011-2013. Data are presented as median (IQR). RESULTS: Infants '(n=77) birth weight was 745 (640 to 960) g and gestational age at birth 26.7 (25.1 to 27.4) weeks. Full enteral feeds were attained by postnatal day 7 (5 to 11). Weight gain from birth to discharge was 14.3 (13.3 to 16.1) g/kg/day, change in SD score for weight -0.03 (-0.55 to 0.46) and 0.09 (-0.78 and 0.82) for head circumference. Rates of necrotising enterocolitis and spontaneous intestinal perforation in all ELGANs admitted during the study period were 3.1% and 9.4%, respectively. CONCLUSIONS: This cohort of ELGANs showed good weight gain and head growth after early full enteral nutrition. The impact of this feeding practice on neonatal morbidity and long-term outcome remains to be tested in adequately powered randomised trials.

Reticulocyte Haemoglobin Content Declines More Markedly in Preterm than in Term Infants in the First Days after Birth.

BACKGROUND: Reticulocyte haemoglobin content, i.e., the reticulocyte equivalent (Ret-He), seems to be a promising parameter for the detection of iron deficiency (ID) in neonates because it can be obtained as part of a reticulocyte count, with no additional blood loss and at no extra cost. Due to the short life span of reticulocytes, Ret-He reflects current iron availability for erythropoiesis more accurately than other common erythrocyte indices. OBJECTIVE: We aimed to evaluate postnatal changes in Ret-He within the first days after birth in term and preterm infants with the hypothesis that preterm infants experience a more pronounced postnatal reduction in Ret-He when compared to term infants. METHODS: We conducted retrospective analyses of clinically indicated blood samples. Paired t test and mixed regression modelling were used. RESULTS: In total, 805 blood samples obtained from 207 term and 295 preterm infants were analysed. Ret-He decreased by 1.5 pg per day (regression coefficient [95% CI] -1.5 [-1.8 to -1.2] pg, p < 0.0001). This drop was more significant in preterm infants (regression coefficient -2.2 [-2.6 to -1.8] pg, p < 0.0001) than in term infants (regression coefficient -0.8 [-1.3 to -0.2] pg, p < 0.01, pinteraction < 0.0001). CONCLUSION: Ret-He declined within the first days after birth. The observed changes with postnatal age were more pronounced in preterm than in term infants. Further studies are needed to evaluate if these changes are due to developing ID or other causes.

Treatment of infants with Syndromic Robin sequence with modified palatal plates: a minimally invasive treatment option.

BACKGROUND: Infants with Robin sequence (RS) suffer from upper airway obstruction (UAO) and feeding problems. We developed an oral appliance with a velar extension in combination with functional treatment and appropriate feeding techniques, which was proven effective in isolated RS. As the above problems are particularly challenging in syndromic RS, we set out to evaluate our treatment concept also in these patients. METHODS: We searched our electronic departmental database to identify all children admitted to our department between 01/01/2003 and 31/12/2009 because of syndromic RS. UAO was quantified by cardiorespiratory sleep studies performed before and during treatment with a modified palatal plate. This appliance consists of a palatal part, covering the hard palate as well as the alveolar ridges and the potential cleft, and a velar extension shifting the tongue in a more anterior position, thereby opening the pharyngeal airway. It is adjusted by fiberoptic nasopharyngoscopy and controlled by cardiorespiratory sleep studies. Obstructive sleep apnea was defined as a mixed obstructive sleep apnea index (MOAI) >3/h. Feeding modalities before and after treatment and weight gain, determined as standard deviation score, were also evaluated. RESULTS: Of 68 children meeting inclusion criteria, 56 completed treatment (46 of these being infants). Underlying diagnoses included craniofacial dysostosis (N = 13) and synostosis syndromes (N = 5), unspecified dysmorphic syndromes (N = 23) and miscellaneous rare conditions (N = 27). Median MOAI decreased from 8.5 (range 0.3-76.0) at admission to 1.1 (0.0-5.2) at discharge (p < 0.001). 51 children received only a TPP and 5 additionally continuous positive airway pressure (CPAP) or high-flow nasal cannula during sleep for mild residual OSA. Three children ultimately required tracheostomy. The number of exclusively gavage fed infants was reduced from 23 to 7. Conversely, the number of children fed exclusively by mouth increased from 18 to 30. Median SDS for weight decreased from -1.6 (-3.5-1.7) to -1.3 (-4.1-2.5). Twelve children had their treatment prematurely discontinued, e.g. due to laryngeal collapse/laryngomalacia. No patient died during treatment. CONCLUSION: Treatment of UAO and feeding problems in these children with syndromic RS by a modified palatal plate with a velar extension was shown to be effective and safe. If confirmed in prospective studies, it may help to avoid more invasive interventions.

Reference Ranges of Reticulocyte Haemoglobin Content in Preterm and Term Infants: A Retrospective Analysis.

BACKGROUND: Despite iron supplementation, some preterm infants develop iron deficiency (ID). The optimal iron status parameter for early detection of ID has yet to be determined. OBJECTIVE: To establish reference ranges for reticulocyte haemoglobin content (Ret-He) in preterm and term infants and to identify confounding factors. METHODS: Retrospective analyses of Ret-He and complete blood count in infants with a clinically indicated blood sample obtained within 24 h after birth. RESULTS: Mean (SD) Ret-He was 30.7 (3.0) pg in very preterm infants with a gestational age (GA) of <30 weeks (n = 55), 31.2 (2.6) pg in moderately preterm infants (GA 30-36 weeks, n = 241) and 32.0 (3.2) pg in term infants (GA ≥37 weeks, n = 216). The 2.5th percentile of Ret-He across all GA groups was 25 pg, with a weak correlation between Ret-He and GA (r = 0.18). Moreover, only weak/no correlations were found between Ret-He and C-reactive protein (r = 0.18), interleukin 6 (IL-6) (r = 0.03) and umbilical artery pH (r = -0.07). There was a slight variation in Ret-He with mode of delivery [normal vaginal delivery: 32.3 (3.2) pg, secondary caesarean section (CS): 31.4 (3.0) pg, instrumental delivery: 31.3 (2.7) pg and elective CS: 31.2 (2.8) pg]. CONCLUSION: GA at birth has a negligible impact on Ret-He, and the lower limit of the normal reference range in newborns within 24 h after birth can be set to 25 pg. Moreover, Ret-He seems to be a robust parameter which is not influenced by perinatal factors within the first 24 h after birth.

Reticulocyte haemoglobin content as a marker of iron deficiency.

OBJECTIVE: To evaluate reticulocyte haemoglobin content (CHr), compared with ferritin, transferrin saturation (TS) and mean corpuscular volume (MCV), as a marker of iron deficiency (ID). DESIGN: Retrospective analysis of clinically indicated blood samples taken between February 2010 and October 2012. SETTING: Single-centre neonatal care unit. PATIENTS: 210 very preterm (gestational age <32 weeks) or very low birthweight infants (birth weight <1500 g) at 3-4 months corrected age. MAIN OUTCOME MEASURES: Complete blood count, CHr, ferritin and TS determined as part of a standard follow-up examination. To detect the optimal CHr cut-off, ID was defined by the presence of more than two of the following three criteria: MCV <75 fL, TS <10%, ferritin <30 µg/L. RESULTS: 210 preterm infants were included at a corrected age of (median (IQR)) 3.5 (3.0-4.0) months and with a CHr of 29.7 (28.6-30.7) pg. There were correlations between CHr and MCV (r=0.54, p <0.0001) and between CHr and TS (r=0.44, p <0.0001). There were 27 (13.4%) iron-deficient infants, and two infants (1%) fulfilled criteria of ID-anaemia. CHr was lower in infants with ID (26.4 (23.8-28.7) pg) than in those without (29.9 (29.0-30.8) pg, p <0.0001). The optimal CHr cut-off for detecting ID was 29 pg (sensitivity 85%, specificity 73%). Areas under the receiver operating characteristic curve for detection of ID tended to be higher for CHr compared with ferritin (0.92 vs 0.75), TS (0.90 vs 0.82) and MCV (0.81 vs 0.72). CONCLUSIONS: CHr seems to be a suitable marker for latent ID in preterm infants at 3-4 months corrected age and may be superior to ferritin, TS and MCV.

Necrotizing enterocolitis and focal intestinal perforation in neonatal intensive care units in the state of baden-württemberg, Germany.

In preterm infants with very low birth weight (VLBW) <1500 g the most important acquired intestinal diseases are necrotising enterocolitis (NEC) and focal intestinal perforation (FIP). We analyzed data of the neonatology module of national external comparative quality assurance for inpatients in the state of Baden-Württemberg, Germany. Between 2010 and 2012, 59 of 3549 VLBW infants developed FIP (1.7%), 128 of them NEC (3.6%). In approximately 3% of infants with BW<1000 g FIP was diagnosed, which was nearly 9 times more often than in infants with BW between 1250 and 1499 g (FIP frequency 0.36%). NEC frequency increased with decreasing BW and was more than 10 times higher in the smallest infants (BW<750 g: 7.87%) compared to those with BW between 1250 and 1499 g (0.72%). The BW limit of 1250 g differentiates between groups of patients with distinguished risks for NEC and FIP.

Choline supply of preterm infants: assessment of dietary intake and pathophysiological considerations.

BACKGROUND: Choline forms the head group of phosphatidylcholines, comprising 40-50 % of cellular membranes and 70-95 % of phospholipids in surfactant, bile, and lipoproteins. Moreover, choline serves as the precursor of acetylcholine and is important for brain differentiation and function. While accepted as essential for fetal and neonatal development, its role in preterm infant nutrition has not yet gained much attention. METHODS: The adequate intake of choline of preterm infants was estimated from international recommendations for infants, children, and adults. Choline intake relative to other nutrients was determined retrospectively in all inborn infants below 1,000 g (extremely low birth weight) or below 28 weeks gestational age, admitted to our department in 2006 and 2007 (N = 93). RESULTS: Estimation of adequate intake showed that children with 290 g body weight need more choline than those with 1,200 g (31.4 and 25.2 mg/kg/day, respectively). Day-by-day variability was high for all nutrient intakes including choline. In contrast to the continuous intrauterine choline delivery, median supply reached a plateau at d11 (21.7 mg/kg/day; 25th/75th percentile: 19.6; 23.9). Individual choline supply at d0-d1 and d2-d3 was <10 mg/kg/day in 100 and 69 % of infants, respectively. Furthermore, intakes <10 mg/kg/day were frequently observed beyond day 11. Median adequate intakes (27.4 mg/kg/day at 735 g body weight) were achieved in <2 %. CONCLUSIONS: Nutritional intake of choline in this cohort of preterm infants was frequently less than the estimated adequate intake, with particular shortage until postnatal d10. Because choline is important for brain development, future studies are needed to investigate the effects of adequate nutritional choline intake on long-term neurodevelopment in VLBW infants.

[The Tübingen palatal plate--an innovative therapeutic concept in Pierre-Robin sequence]. / Die Tübinger Gaumenplatte--Ein innovatives Therapiekonzept bei Pierre-Robin-Sequenz.

Infants with Pierre-Robin sequence (PRS) may suffer severe upper airway obstruction resulting in hypoxemia that is difficult to treat. We are currently evaluating a new therapeutic approach involving an oral appliance that widens the pharynx by pulling the base of the tongue forward using a preepiglottic baton. Here we present a patient treated with this device who showed a decrease in his desaturation index from 50 to < 1.