Neonatal Sepsis and Hemostasis.

Neonatal sepsis is considered critical for a significant increase in neonatal morbidity and mortality among hospitalized neonates. Neonatal sepsis, in most cases, coexists with coagulopathy, which can prove to be life-threatening. Complex molecular and cellular systems are involved in the cross-talk between inflammation and hemostasis during sepsis. Disturbances in the regulating systems of the vascular endothelium, and platelet-endothelial and platelet-neutrophil interactions play a pivotal role in both inflammation and coagulation. This complex process is poorly understood in neonates. In addition to the developmental maturation of hemostasis and the immune response in neonatal sepsis, a cellular model of hemostasis during sepsis should be taken into account. This review focused on the molecular and cellular mechanisms underlying inflammation and hemostasis during neonatal sepsis, taking the developmental immune response and developmental hemostasis into account in order to provide future diagnostic approaches to be applied in everyday clinical settings. Regarding the diagnostic modalities, we briefly provide the limitations of the currently used conventional coagulation assays, focusing on viscoelastic tests and platelet flow cytometry.

Clinical chorioamnionitis and histologic placental inflammation: association with early-neonatal sepsis.

OBJECTIVE: Chorioamnionitis and fetal inflammatory response syndrome (FIRS) are significant risk factors for early onset sepsis (EOS). Recently, the use "Intrauterine Inflammation or Infection or both" or triple I has been proposed, classifying cases into an isolated maternal fever, suspected triple I, or confirmed chorioamnionitis. Evidence suggests that the association between suspected chorioamnionitis and confirmed histological chorioamnionitis (HCA) is not consistent, as well as the impact of HCA on the development of EOS.We aimed to evaluate the association between suspected chorioamnionitis and HCA, the impact of HCA on EOS, and the effect of antepartum antibiotic prophylaxis on EOS. METHODS: We retrospectively reviewed the medical records of all infants admitted to our institution, between 2017 and 2018, with a diagnosis of chorioamnionitis. We recorded the clinical evidence of chorioamnionitis, the histologic report of the placenta, the maternal and neonatal data, the neonatal inflammatory markers including C-reactive protein (CRP), and the incidence of EOS. The impact of antepartum antibiotic prophylaxis on the infants' CRP and EOS was calculated, and the logistic regression model was performed to estimate the association of confirmed HCA with EOS, while controlling for FIRS stage, gestation age, birth weight, maternal fever, foul-smelling amniotic fluid, and prolonged rupture of membranes. RESULTS: During the study period, a total of 266 infants were identified; 81 (30%) infants had a confirmed HCA (HCA-present cases), and 185 (70%) infants were diagnosed with suspected triple I (HCA-absent cases). Antepartum antibiotics had been commenced in a significantly higher proportion in HCA-present cases (46%) in comparison to 14% of HCA-absent cases (p < .001). HCA-present infants were of significantly lower gestation (31.6 ± 4weeks versus 33.3 ± 4weeks, p = .004), and birth weight (1826 ± 840 g versus 2092 ± 849 g, p = .019), they had a significantly higher rate of clinical symptoms (31% versus 6%, p < .001), and a higher CRP at birth and 24 h (1.4 ± 1.5 mg/dL versus 0.3 ± 0.2 mg/dL, p < .001, and 2.1 ± 2.3 mg/dL versus 0.4 ± 0.6 mg/dL, p < .001, respectively). All HCA-present cases had evidence of FIRS; 43% were stage I, 25% stage II, and 32% were FIRS stage III. A significantly higher proportion of HCA-present infants were diagnosed with EOS (46% as compared to 6%, p < .001). The antepartum antibiotic administration was related to a significantly lower CRP at birth and 24 h only in HCA-present cases, albeit not with any reduction ιn EOS incidence. HCA was significantly associated with EOS (RR 3.18, 95% CI 2.81-5.18, p < .001). After adjusting for perinatal factors, the presence of HCA (OR 7.89, 95% CI 1.19-23.34, p = .032) and an advanced FIRS stage (OR 10.35, 95% CI 4.23-25.32, p < .001) were significantly associated with EOS. CONCLUSIONS: Amongst infants with suspected chorioamnionitis, the diagnosis is partially supported by histological confirmation, and that is more prominent in pregnancies of a lower gestation. The presence of HCA and an advanced FIRS stage predispose to an increased risk of EOS after adjusting for other perinatal and neonatal factors. The antepartum prophylaxis against intra-amniotic infection was related to a significantly lower CRP in HCA-present cases.

G6PD deficiency and Harilaou variant in a newborn: Intrauterine haemolysis and meconium aspiration syndrome.

G6PD deficiency is one of the most commonly inherited enzymopathies with a hallmark of an X-linked pattern. G6PD has more than 300 unique variants with different enzyme activity. The G6PD Mediterranean variant is prevalent in Greece and associated with asymptomatic patients who may experience haemolysis under specific circumstances. G6PD Harilaou is a new variant that was first described in Greece in an eight-year-old boy who suffered chronic haemolysis demanding multiple transfusions. We present a new case of the G6PD Harilaou variant in a Greek male neonate who suffered severe intrauterine haemolysis and passed away 39 hours after birth. To our knowledge, it is the second reported G6PD Harilaou case.

The Intertemporal Role of Respiratory Support in Improving Neonatal Outcomes: A Narrative Review.

Defining improvements in healthcare can be challenging due to the need to assess multiple outcomes and measures. In neonates, although progress in respiratory support has been a key factor in improving survival, the same degree of improvement has not been documented in certain outcomes, such as bronchopulmonary dysplasia. By exploring the evolution of neonatal respiratory care over the last 60 years, this review highlights not only the scientific advances that occurred with the application of invasive mechanical ventilation but also the weakness of the existing knowledge. The contributing role of non-invasive ventilation and less-invasive surfactant administration methods as well as of certain pharmacological therapies is also discussed. Moreover, we analyze the cost-benefit of neonatal care-respiratory support and present future challenges and perspectives.

Changes in Physicians' Perceptions and Practices on Neonatal Pain Management Over the Past 20 Years. A Survey Conducted at Two Time-Points.

Intense research for more than three decades expelled the view that neonates do not experience pain. The aim of this survey was to investigate whether the Greek physicians involved in neonatal intensive care have changed their perceptions regarding neonatal pain, adapting their management practices to the knowledge that have emerged in the past 20-years. This study is a survey conducted at two time-points, 20 years apart. Anonymous questionnaires were distributed to 117 and 145 physicians working in neonatal intensive care units (NICUs) all over Greece in years 2000 and 2019, respectively. The response rate was 90.6 and 80.7% in 2000 and 2019, respectively. All respondents, at both time-points, believed that neonates experience pain, which has serious acute and long-term consequences, while the vast majority considered analgesia-sedation (A-S) during painful interventions as obligatory. Utilization of NICU protocols and pain assessment tools remained low although increased significantly between 2000 and 2019. The use of systemic A-S postoperatively was high at both time-points, while its implementation in infants subjected to prolonged pain, specifically mechanical ventilation, increased significantly by 2019. Systemic or local analgesia for acute procedural pain was used by lower proportions of physicians in 2019, except for the tracheal intubation. In contrast, the use of sweet solutions and non-pharmacological measures prior to or during bedside procedures significantly increased over time. Opioid administration significantly increased, while a shift from morphine to fentanyl was observed. International literature and perinatal-neonatal congresses were stated as the main sources of updating physicians' knowledge and improving management practice on neonatal pain prevention and treatment. In conclusion, Greek NICU-physicians' perceptions that neonates can experience pain with potentially serious acute and long-term consequences remained strong over the past 20 years. Although physicians' practices on neonatal pain management improved, they are still suboptimal, while significant differences exist among centers. Continuing education, globally accepted management protocols, and readily applied pain assessment tools would further improve the management of procedural pain and stress in neonates.

Are neonatal outcomes of triplet pregnancies different from those of singletons according to gestational age?

OBJECTIVES: Multiple pregnancies sustain the high pace of extreme prematurity. Little evidence is available about triplet gestation given the evolution in their management during the last decades. The aim of the study was to compare the neonatal outcomes of triplets with those of matched singletons in a cohort study. METHODS: An observational retrospective cohort study of triplets and matched singletons born between 2004 and 2017 matched by gestational age was conducted. Additionally, the investigation performed in regard to data from the overall Greek population of interest. The primary outcome was mortality or severe neonatal morbidity based on pregnancy type. RESULTS: A total of 237 triplets of 24-36 weeks' gestation and 482 matched singletons were included. No differences in the primary outcome between triplets and singletons were found. Rates of severe neonatal morbidities did not differ significantly between triplets and singletons. A threshold of 1000 gr for birthweight and 28 weeks' gestation for gestational age determined survival on triplets [OR: 0.08 (95% CI: 0.02-0.40, p=0.0020) and OR: 0.13 (95% CI: 0.03-0.57, p=0.0020) for gestational age and birthweight respectively]. In Greece stillbirths in triplets was 8 times higher than that of singletons (OR: 8.5, 95% CI: 6.9-10.5). From 3,375 triplets, 94 were stillborn, whereas in singletons, 4,659 out of 1,388,273. In our center 5 times more triplets than the expected average in Greece were delivered with no significant difference in stillbirths' rates. CONCLUSIONS: No significant differences were identified in mortality or major neonatal morbidities between triplets and matched singletons highlighting the significance of prematurity and birthweight for these outcomes.

Minimal invasive surfactant therapy in preterm infants with respiratory distress syndrome: a single center experience.

BACKGROUND: Minimal invasive surfactant therapy (MIST) includes the tracheal instillation of surfactant via a thin catheter for the treatment of preterm infants with respiratory distress syndrome (RDS). We aimed to evaluate the impact of MIST compared to intubation, surfactant, extubation (INSURE) technique on respiratory outcomes. METHODS: A prospectively recruited cohort of preterm infants ≤32 weeks with RDS was compared against a historical cohort of infants treated with INSURE. The primary outcome was the need for mechanical ventilation within 72 hours of age and secondary outcomes the overall need and duration of mechanical ventilation, the development of bronchopulmonary dysplasia, common morbidities, and survival. RESULTS: Thirty-six infants treated with MIST of 29.1±2.2 weeks' gestation and 1219±238 grams' birthweight compared against 37 infants of 28.8±2.3 weeks' gestation and 1195±336 grams' birthweight treated with INSURE. A lower proportion of infants treated with MIST required mechanical ventilation within 72 hours of age compared to those treated with INSURE (11% compared 32%, p=0.042). However, no significant differences were noted regarding the overall intubation incidence, bronchopulmonary dysplasia, other morbidities, or survival. CONCLUSIONS: In spontaneously breathing infants ≤32 weeks with RDS, the MIST technique was associated with a lower need for intubation within 72 hours of age, but otherwise with no significant differences regarding BPD or other neonatal morbidities.

A neonate with intrauterine growth restriction and pseudo-Bartter syndrome due to severe maternal eating disorder: A case report.

Maternal diet before and during pregnancy plays an important role for the developing fetus. Any eating disorder in this period can cause transient or/and permanent negative effects on the mother and her offspring.

Evaluation of cerebral oxygenation and perfusion in small for gestational age neonates and neurodevelopmental outcome at 24-36 months of age.

Objective To examine cerebral oxygenation and perfusion in small for gestational age (SGA) compared with appropriate for gestational age (AGA) neonates during the first postnatal week, and to investigate any association with neurodevelopmental outcomes at 24-36 months of age. Methods A prospective matched case-control study was conducted evaluating cerebral oxygenation and perfusion, using near-infrared spectroscopy (NIRS), between SGA and AGA neonates, during the first postnatal week. A neurodevelopmental assessment with Bayley-III was performed at 24-36 months of age. Results Forty-eight SGA and 48 AGA neonates of similar gestation (32.8 ± 2.1 vs. 32.5 ± 1.9) were enrolled. On the first postnatal day, the cerebral oxygenation was equal between SGA and AGA neonates (71 ± 7% vs. 72 ± 8%); however, in the subgroup analysis, males had higher oxygenation compared to female SGA neonates (73 ± 7% vs. 69 ± 7%, P = 0.04). Cerebral perfusion was significantly higher in SGA neonates on the first postnatal day (1.4 ± 0.6 vs. 1.1 ± 0.5, P = 0.04), but this difference was diminished on subsequent measurements. There were no significant differences between the SGA and AGA infants regarding the composite cognitive, communication and motor index scores. The length of mechanical ventilation and late-onset sepsis were significant risk factors affecting the cognitive and communication composite index scores, respectively. Conclusion Cerebral oxygenation was equal between SGA and AGA neonates, while cerebral perfusion was transiently increased in SGA neonates during the first postnatal day. There was no significant association of cerebral oxygenation and perfusion with neurodevelopmental outcomes.

Retinopathy of prematurity occurrence and evaluation of screening policy in a large tertiary Greek cohort.

PURPOSE: To assess the frequency of retinopathy of prematurity (ROP) and evaluate the appropriateness of screening guidelines in a tertiary hospital in Thessaloniki, Greece. METHODS: Retrospective review of consecutive infants admitted to the IInd Department of the Neonatal Care Unit of Aristotle University in the period April 2004-2015. ROP screening took place according to the Royal College of Paediatrics and Child Health and Royal College of Ophthalmologists (UK) guidelines [i.e. gestational age < 32 weeks and/or birth weight < 1501 g)], plus a few additional cases due to comorbidity. RESULTS: 1178 out of the 8782 admitted infants underwent ROP screening. ROP was detected in 232 (19.7%) infants of whom 87 developed severe form of the disease (i.e. ≥ stage 3). Treatment was required in 30 (2.5%) infants, all of whom fulfilled the screening criteria. Two of the 206 infants who were additionally screened due to comorbidity developed severe ROP which regressed spontaneously. Disease regression was achieved in 27/29 (93%) treated infants who survived. CONCLUSIONS: The frequency of ROP observed in this cohort was as low as that reported in other developed countries. The currently used screening criteria permitted identification of all infants who were at risk and, therefore, need not be changed.

A New ABCA3 Gene Mutation c.3445G>A (p.Asp1149Asn) as a Causative Agent of Newborn Lethal Respiratory Distress Syndrome.

Mutations in adenosine triphosphate-binding cassette transporter A3 (ABCA3) (OMIM: 601615) gene constitute the most frequent genetic cause of severe neonatal respiratory distress syndrome (RDS) and interstitial lung disease (ILD) in children. Interstitial lung disease in children and especially in infants, in contrast to adults, is more likely to appear as a result of developmental deficits or is characterized by genetic aberrations of pulmonary surfactant homeostasis not responding to exogenous surfactant administration. The underlying ABCA3 gene mutations are commonly thought, regarding null mutations, to determine the clinical course of the disease while there exist mutation types, especially missense variants, whose effects on surfactant proteins are difficult to predict. In addition, clinical and radiological signs overlap with those of surfactant proteins B and C mutations making diagnosis challenging. We demonstrate a case of a one-term newborn male with lethal respiratory failure caused by homozygous missense ABCA3 gene mutation c.3445G>A (p.Asp1149Asn), which, to our knowledge, was not previously reported as a causative agent of newborn lethal RDS. Therapeutic strategies for patients with ABCA3 gene mutations are not sufficiently evidence-based. Therefore, the description of the clinical course and treatment of the disease in terms of a likely correlation between genotype and phenotype is crucial for the development of the optimal clinical approach for affected individuals.

The association of the cerebral oxygenation during neonatal sepsis with the Bayley-III Scale of Infant and Toddler Development index scores at 18-24 months of age.

BACKGROUND: Neonatal sepsis has been associated with poor neurodevelopmental outcome, however the evidence regarding the exact mechanism of the inflammation to the developing neonatal brain are inconclusive. AIMS: To investigate association between cerebral oxygenation during neonatal sepsis and neurodevelopmental outcome. STUDY DESIGN: Follow-up assessment of a previously described prospective case-control study. SUBJECTS: A cohort of late preterm (34-37 weeks' gestation) and preterm (<34 weeks' gestation) infants with sepsis and healthy controls, evaluated at 18-24 months of corrected gestational age with Bayley-III Scales for Infant and Toddler Development (BSID-III). OUTCOME MEASURES: To evaluate the association between cerebral tissue oxygenation index (cTOI) and fractional tissue oxygen extraction (FTOE), measured with near-infrared spectroscopy, during sepsis and the composite cognitive and motor index scores. RESULTS: Thirty-one infants with blood culture confirmed neonatal sepsis and thirty-five controls were recruited. The cerebral oxygenation was significantly lower in septic neonates, compared to controls (61 ±â€¯7 compared to 72 ±â€¯5; p < 0.001). Infants with sepsis had significantly lower cognitive and motor index scores and higher proportion of suboptimal cognitive (16% compared to 3%, p = 0.045) and motor (16% compared to none, p = 0.008) index score. The low mean cTOI and FTOE noted in septic infants were significantly associated with worse cognitive and motor composite index scores. CONCLUSIONS: Infants with lower cerebral oxygenation during neonatal sepsis are at increased risk of worse cognitive and motor scores in the neurodevelopmental assessment.

Early caloric deprivation in preterm infants affects Bayley-III scales performance at 18-24 months of corrected age.

BACKGROUND: Adequate nutrition is essential for optimal neurodevelopment to preterm infants. Our aim was to evaluate the impact of caloric deprivation on Bayley-III scales performance at 18-24 months of corrected age, in a cohort of preterm infants. METHODS: We prospectively enrolled infants with gestational age <30 weeks and birth weight <1500 g. Apart from a whole cohort analysis, we performed a subgroup analysis between infants received inadequate calories (<85 Kcal/kg/day) during the first two weeks of age, compared to a standard nutrition group. All infants underwent a Bayley-III assessment at 18-24 months of corrected age. RESULTS: From the 63 preterm infants analysed, 25% had caloric deprivation compared to 75% with adequate nutrition. Caloric deprived infants were of lower gestational age and birth weight, and received a lower amount of enteral feeding during the first 14 days of age. There were no differences between the two groups regarding the common neonatal co-morbidities. Caloric deprived infants had significantly lower composite index scores at 18-24 months of corrected age. Caloric deprivation, late onset sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia were significant risk factors of neurodevelopmental impairment. CONCLUSIONS: Several neonatal factors affect the neurodevelopmental outcome of preterm infants, and nutrition may pose an important role.

Evaluation of Cerebral Oxygenation in Neonates with Sepsis with Near-Infrared Spectroscopy.

Objective Neonates with sepsis have increased risk of cerebral injury. Our aim was to evaluate cerebral oxygenation in septic neonates using near-infrared spectroscopy. Study Design A prospective study was designed enrolling neonates with sepsis, as defined by the International Consensus Conference of Pediatric Sepsis criteria and matched controls. Three cerebral half-hourly measurements were performed during the first, third, and seventh day of the episode and the values of tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were compared between the two groups. Result The study population consisted of 50 septic and 44 control neonates with similar characteristics. No differences on TOI and FTOE were recorded in the first and third day. However, on the seventh day, septic neonates had significantly decreased oxygenation (62.7 ± 7 vs. 71.4 ± 4.4%, p < 0.001) and increased oxygen extraction (0.35 ± 0.07 vs. 0.27 ± 0.05, p < 0.001), irrespectively of the severity of the infection. Conclusion Although septic neonates have normal cerebral oxygenation in the first and third day of the sepsis, they present decreased cerebral oxygenation in the seventh day independently of the infection severity.

Intraventricular Hemorrhage and Platelet Indices in Extremely Premature Neonates.

Intraventricular hemorrhage (IVH) is a multifactorial disorder, the most important risk factors of which are prematurity and low birth weight. Disturbances in cerebral blood flow, inherent fragility of the germinal matrix vasculature, and platelet/coagulation disturbances are the 3 major pathogenic mechanisms. In this context, we investigated the role of platelet indices and several maternal and neonatal characteristics in the development of IVH through a retrospective cohort analysis of 130 extremely premature neonates, 24% of whom presented with severe IVH. There was a significant difference in platelet counts between the IVH and the control group on the first day of life (P=0.046). Presence of IVH was linked with lower birth weight (P=0.006) and lower gestational age (P=0.001). Platelet count on the first day of life was positively correlated with survival (P=0.001) and, along with platelet mass, was indicative of the worst IVH grade recorded for each neonate (P=0.002 and 0.007, respectively). Prolonged prothrombin time was also correlated with IVH (P<0.001), but factor analysis supported no prominent role. Maternal medications seem to play a minor role as well. In conclusion, IVH in extremely premature infants cannot be solely explained by platelet parameters, and further studies are required to determine the relationships between IVH, platelet indices, and outcomes.

Intraventricular Hemorrhage and Platelet Indices in Extremely Premature Neonates.

Intraventricular hemorrhage (IVH) is a multifactorial disorder, the most important risk factors of which are prematurity and low birth weight. Disturbances in cerebral blood flow, inherent fragility of the germinal matrix vasculature, and platelet/coagulation disturbances are the 3 major pathogenic mechanisms. In this context, we investigated the role of platelet indices and several maternal and neonatal characteristics in the development of IVH through a retrospective cohort analysis of 130 extremely premature neonates, 24% of whom presented with severe IVH. There was a significant difference in platelet counts between the IVH and the control group on the first day of life (P=0.046). Presence of IVH was linked with lower birth weight (P=0.006) and lower gestational age (P=0.001). Platelet count on the first day of life was positively correlated with survival (P=0.001) and, along with platelet mass, was indicative of the worst IVH grade recorded for each neonate (P=0.002 and 0.007, respectively). Prolonged prothrombin time was also correlated with IVH (P<0.001), but factor analysis supported no prominent role. Maternal medications seem to play a minor role as well. In conclusion, IVH in extremely premature infants cannot be solely explained by platelet parameters, and further studies are required to determine the relationships between IVH, platelet indices, and outcomes.

Recurrent giant cell fibroblastoma: Malignancy predisposition in Kabuki syndrome revisited.

Kabuki syndrome is a genetic condition characterized by distinctive facial phenotype, mental retardation, and internal organ malformations. Mutations of the epigenetic genes KMT2D and KDM6A cause dysregulation of certain developmental genes and account for the multiple congenital anomalies of the syndrome. Eight cases of malignancies have been reported in young patients with Kabuki syndrome although a causative association to the syndrome has not been established. We report a case of a 12-year-old girl with Kabuki syndrome who developed a tumor on the right side of her neck. A relapsing tumor 19 months after initial excision, proved to be giant cell fibroblastoma. Τhis is the first report of giant cell fibroblastoma -a rare tumor of childhood- in a patient with Kabuki syndrome.

Significant reduction of central line-associated bloodstream infection rates in a tertiary neonatal unit.

To evaluate the effectiveness of a quality initiative in reducing central line-associated bloodstream infections (CLABSIs) in our neonatal intensive care unit, we designed a prospective study (January 2012-September 2013) estimating CLABSI incidence before and after our implementation. CLABSI rates were significantly decreased after our intervention, from 12 cases per 1,000 central vascular catheter (CVC) days during the preinterventional period to 3.4 cases per 1,000 CVC days during the postinterventional period (P = .004).

Correlation of brain ultrasonography scans to the neuromotor outcome of very-low-birth-weight infants during the first year of life.

To evaluate the consistency of the Hammersmith Infant Neurological Examination scores of very-low-birth-weight infants at 6 and 12 months of age and its correlation to cranial ultrasonography findings, we designed a prospective study between January 2005 and January 2008, in the tertiary Neonatal Unit of Aristotle University of Thessaloniki, Greece. All infants enrolled had a cranial ultrasonography performed at term. Preterm infants born at <32 weeks gestation with a birth weight <1500 g were eligible for the study. One hundred seventy-four infants were finally enrolled; out of those, 46 (26%) had an optimal score at 6 and 76 (44%) at 12 months of age. Mean global scores were 61 and 69 at 6 and 12 months, respectively. The Hammersmith Infant Neurological Examination score significantly increased between 6 and 12 months, equally in all ultrasonography groups. The presence of cystic periventricular leukomalacia was associated to lower scores and neurologic impairment.