Joint Laxity in Preschool Children Born Preterm.

OBJECTIVE: To evaluate the prevalence of joint laxity in children born preterm assessed in the first 2 years, the relationship between joint laxity and motor performance at preschool age, and possible changes over time in a subgroup of children followed longitudinally. STUDY DESIGN: The revised scale of Beighton Score was used to evaluate joint laxity in a population of 132 preschool children born preterm between 24 and 32 weeks of gestational age. All were assessed for joint laxity between 12 and 24 months of age. Children also performed the Movement Assessment Battery for Children-Second Edition between the age of 3 years and 6 months and 4 years; the age at onset of independent walking also was recorded. RESULTS: The total Beighton Score ranged between 0 and 8. Twenty percent of the cohort showed joint laxity. No differences related to sex or gestational age were observed. Children born preterm with joint laxity achieved later independent walking and achieved lower scores on Movement Assessment Battery for Children-Second Edition than those without joint laxity. In 76 children born preterm, an assessment for joint laxity was repeated once between 25 and 36 months and again after >36 months. No statistically significant difference was observed between the 3 assessments. CONCLUSIONS: The Beighton Score can be used to assess generalized joint laxity in children born preterm. As the presence of joint laxity influenced motor competences, the possibility to early identify these infants in the first 2 years is of interest to benefit from early intervention and potentially improve gross motor skills and coordination.

Chrono-proteomics of human saliva: variations of the salivary proteome during human development.

An important contribution to the variability of any proteome is given by the time dimension that should be carefully considered to define physiological modifications. To this purpose, whole saliva proteome was investigated in a wide age range. Whole saliva was collected from 17 preterm newborns with a postconceptional age at birth of 178-217 days. In these subjects sample collection was performed serially starting immediately after birth and within about 1 year follow-up, gathering a total of 111 specimens. Furthermore, whole saliva was collected from 182 subjects aged between 0 and 17 years and from 23 adults aged between 27 and 57 years. The naturally occurring intact salivary proteome of the 316 samples was analyzed by low- and high-resolution HPLC-ESI-MS platforms. Proteins peculiar of the adults appeared in saliva with different time courses during human development. Acidic proline-rich proteins encoded by PRH2 locus and glycosylated basic proline-rich proteins encoded by PRB3 locus appeared following 180 days of postconceptional age, followed at 7 months (±2 weeks) by histatin 1, statherin, and P-B peptide. The other histatins and acidic proline-rich proteins encoded by PRH1 locus appeared in whole saliva of babies from 1 to 3 weeks after the normal term of delivery, S-type cystatins appeared at 1 year (±3 months), and basic proline-rich proteins appeared at 4 years (±1 year) of age. All of the proteinases involved in the maturation of salivary proteins were more active in preterm than in at-term newborns, on the basis of the truncated forms detected. The activity of the Fam20C kinase, involved in the phosphorylation of various proteins, started around 180 days of postconceptional age, slowly increased reaching values comparable to adults at about 2 years (±6 months) of age. Instead, MAPK14 involved in the phosphorylation of S100A9 was fully active since birth also in preterm newborns.

Determination of Lung Volume and Hemodynamic Changes During High-Frequency Ventilation Recruitment in Preterm Neonates With Respiratory Distress Syndrome.

OBJECTIVES: To evaluate the changes in end-expiratory lung volume during an oxygenation-guided stepwise recruitment procedure in elective high-frequency ventilation. We hypothesized that high continuous distending pressure impedes pulmonary blood flow as evidenced by reduced lung volume measurements using respiratory inductive plethysmography. Changes in oxygenation, ventilation, and peripheral perfusion were evaluated as secondary outcomes. DESIGN: A prospective, single center, observational, nonrandomized study. SETTING: The study was conducted in a neonatal ICU in Italy. PATIENTS: High-frequency ventilated preterm infants with respiratory distress syndrome. INTERVENTIONS: During the recruitment procedure, end-expiratory lung volume measured by respiratory inductive plethysmography, oxygen saturation, perfusion index, regional cerebral and perirenal tissue oxygenation, heart rate, transcutaneous PCO2, and tidal volume were simultaneously recorded at each airway pressure step. MEASUREMENTS AND MAIN RESULTS: In 12 preterm newborns (gestational age, 27.4 ± 0.2 wk; birth weight, 979 ± 198 g), high-frequency ventilation was initiated at a continuous distending pressure of 10 cm H2O and incrementally increased by 1-2 cm H2O every 2-5 minutes until FIO2 was less than or equal to 0.25. End-expiratory lung volume progressively increased during the initial recruitment, but decreased at the maximum airway pressure in nine patients, indicative of a reduction in pulmonary perfusion. At the end of recruitment, tidal volume was significantly higher (p = 0.002) and oxygenation was significantly improved (p = 0.002); however, mean perfusion index, postductal saturation, and mean renal tissue oxygenation values were significantly reduced (p < 0.05) compared with baseline. Mean cerebral tissue oxygenation and mean transcutaneous PCO2 values were reduced but failed to reach significance. CONCLUSIONS: High distending lung pressures increased oxygenation but decreased peripheral perfusion with no adverse cerebral side effects. Coupled with the reduction in respiratory inductive plethysmography-derived lung volume, high continuous distending pressure had adverse cardiopulmonary effects. Incorporation of lung volume and hemodynamic and oxygenation variables may guide optimum lung volume determination during high-frequency ventilation recruitment procedure while preventing adverse effects on the pulmonary circulation.

Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings.

PURPOSE: To compare the structural outcome at 9 months of eyes treated with intravitreal injection of bevacizumab with fellow eyes treated with conventional laser photoablation in zone I type 1 retinopathy of prematurity (ROP). DESIGN: Single randomized controlled trial. PARTICIPANTS: All inborn babies with type 1 zone I ROP at a single institution were included in the study. One eye was randomized to receive an intravitreal injection of 0.5 mg bevacizumab; the fellow eye received conventional laser photoablation. METHODS: Digital fundus photographs and fluorescein angiography (FA) using the RetCam (Clarity Medical Systems Inc., Pleasanton, CA) were performed before treatment and 9 months after treatment. MAIN OUTCOME MEASURES: Presence of retinal and choroidal abnormalities on FA at 9 months. RESULTS: Thirteen infants were enrolled; 1 died 3 months after birth. One laser-treated eye progressed to stage 5 retinal detachment. The remaining 23 eyes had favorable structural results at the 9-month follow-up and provided FA results. At 9 months of age, all eyes treated with a bevacizumab injection were noted to have abnormalities at the periphery (large avascular area, abnormal branching, shunt) or the posterior pole (hyperfluorescent lesion, absence of foveal avascular zone). These posterior and peripheral lesions were not observed in the majority of the lasered eyes. CONCLUSIONS: This study documents significant vascular and macular abnormalities of eyes in the bevacizumab group. Long-lasting implications of these abnormalities for visual function of the child need to be studied.

Top-down HPLC-ESI-MS detection of S-glutathionylated and S-cysteinylated derivatives of cystatin B and its 1-53 and 54-98 fragments in whole saliva of human preterm newborns.

Analysis by a HPLC-ESI-MS top-down proteomic platform of specimens of human preterm newborn whole saliva evidenced high relative amounts of cystatin B and its S-glutathionylated,S-cysteinylated, and S-S 2-mer (on Cys(3)) derivatives, decreasing as a function of postconceptional age (PCA). The percentage of S-unmodified cystatin B was higher than the S-modified isoforms in the early PCA period, differently from adults where cystatin B was detectable only as S-modified derivatives. The percentage of S-modified derivatives increased as a function of PCA, reaching at the normal term of delivery values similar to those determined in at-term newborns, babies, and adults. Moreover, in the early PCA period, high relative amounts of the 1-53 and 54-98 cystatin B fragments were detected, decreasing as a function of PCA and disappearing at the normal term of delivery. In agreement with intact cystatin B, fragment 1-53 was detectable as S-unmodified and S-modified derivatives, and their percentages changed accordingly with the percentages of intact proteins, suggesting that the fragmentation process could be subsequent to and independent from the S-modification of the protein. This study highlights specific enzymatic activity in the oral cavity of preterm newborns not present in at-term newborns and adults, which can be a clue to specialized pathways occurring during fetal oral development.

Association of high levels of α-defensins and S100A proteins with Candida mannan detection in bronchoalveolar lavage fluid of preterm neonates.

BACKGROUND: Candida mannan (Mn) detection in bronchoalveolar lavage fluid (BALF) was shown to be useful for earlier identification and preemptive therapy targeting in preterm infants at high risk of invasive Candida infection. We investigated whether early detection of Candida Mn in BALF is associated with the presence of some neutrophilic products, as markers of prenatal infection/inflammation. METHODS: BALF specimens were collected during the first 48 h of life from mechanically ventilated preterm newborns. Samples were analyzed by high-performance liquid chromatography-electrospray ionization-mass spectrometry. The relative amounts of α-defensins 1-4 and S100A proteins were measured by extracted ion current peak area. Absolute and differential white cell counts in BALF were obtained. Mn antigen concentrations were determined by the Platelia Candida antigen kit. RESULTS: Twenty-five studied neonates were divided into two groups: Mn-positive group and Mn-negative group. Levels of α-defensins 1-4 and S100A12 were significantly higher in the Mn-positive group than in the Mn-negative group. Moreover, positive significant correlations between the absolute number of neutrophils and the levels of α-defensins 1-4 and S100A8 were observed. CONCLUSION: The detection of Mn antigen in BALF of preterm infants is consistent with evidence of an innate immune response in their lungs as demonstrated by higher levels of α-defensins and S100A proteins.

Anti-Rh(c), "little c," isoimmunization: the role of rHuEpo in preventing late anemia.

The overall prevalence of non-Rh-D isoimmunization seems to lie between 0.15% and 1.1%. Anti-Rh(c) alloimmunization, "little c," occurs in 0.07% of pregnancies and shows a quite broad clinical presentation. Late anemia is a frequent problem occurring in the setting of isoimmunization. It occurs more frequently after intrauterine blood transfusions or exsanguinotransfusion, and it can be thought as a hyporegenerative anemia. The authors describe the use of human recombinant erythropoietin in preventing late anemia in a case of anti-Rh(c) isoimmunization. The use of human recombinant erythropoietin is a valid tool for preventing late-onset anemia due to either anti-Rh-D or non-anti-Rh-D isoimmunization.

The surprising composition of the salivary proteome of preterm human newborn.

Saliva is a body fluid of a unique composition devoted to protect the mouth cavity and the digestive tract. Our high performance liquid chromatography (HPLC)-electrospray ionization-MS analysis of the acidic soluble fraction of saliva from preterm human newborn surprisingly revealed more than 40 protein masses often undetected in adult saliva. We were able to identify the following proteins: stefin A and stefin B, S100A7 (two isoforms), S100A8, S100A9 (four isoforms), S100A11, S100A12, small proline-rich protein 3 (two isoforms), lysozyme C, thymosins ß(4) and ß(10), antileukoproteinase, histone H1c, and α and γ globins. The average mass value reported in international data banks was often incongruent with our experimental results mostly because of post-translational modifications of the proteins, e.g. acetylation of the N-terminal residue. A quantitative label-free MS analysis showed protein levels altered in relation to the postconceptional age and suggested coordinate and hierarchical functions for these proteins during development. In summary, this study shows for the first time that analysis of these proteins in saliva of preterm newborns might represent a noninvasive way to obtain precious information of the molecular mechanisms of development of human fetal oral structures.

How to administrate erythropoietin, intravenous or subcutaneous?

AIM: To determine whether adding recombinant erythropoietin to the intravenous (IV) solution and administering it as a 24-h continuous infusion would result in an erythropoietic effect not inferior to that seen with subcutaneous (SC) administration. METHODS: Infants weighing ≤1500 grams and ≤32 weeks of gestational age were randomly assigned at 72 h of life to receive erythropoietin (300 units/kg, 3 times a week until 36 complete weeks of postmenstrual age or discharge), either subcutaneously [erythropoietin subcutaneous (ESC) group] or added to IV fluids [erythropoietin intravenous (EIV) group]. RESULTS: One hundred infants were randomized (50 in the EIV group and 50 in the ESC group). The incidence of transfusions was comparable in the two groups, similar in baseline characteristics and haematologic values at study entry. Phlebotomy losses did not differ between groups, and at the end of the study, there were no differences in reticulocyte counts, transferrin saturation and ferritin. No differences in the incidence of side effects were observed. CONCLUSIONS: In preterm infants, continuous intravenous administration of erythropoietin was not inferior to SC dosing.

Heat loss prevention in the delivery room in term and preterm infants.

This study was conducted to determine whether or not simultaneous use of additional measures to prevent heat loss and efficient training of caregivers influenced the incidence of hypothermia at birth. Two cohorts of term/late-preterm and preterm infants were compared before (Group IA and IB) and after (Group IIA and IIB) the introduction of additional measures and a specific training of caregivers. In term/late-preterm neonates of Group IIA, admission temperature was higher (36.3°C vs 36°C; p<0.001) and incidence of hypothermia lower (61.2% vs 81.0%; p<0.001) compared to Group IA, with reduction of moderate hypothermia (8.8% vs 27.3%; p<0.001). Among preterm neonates, admission temperature was higher (36.0°C vs 35.5°C; p<0.001) and incidence of hypothermia lower (68.1% vs 92.3%; p<0.001) during the second period, when no cases of severe hypothermia and reduction of moderate forms were observed (42.5% vs 70.7%; p<0.001). Additional interventions to prevent hypothermia and caregivers' training were effective in preventing hypothermia.

Efficacy of exogenous surfactant during conventional and high-frequency oscillatory ventilation in preterm infants with RDS.

INTRODUCTION: The immediate effects of exogenous surfactant on lung volume and hemodynamics in preterm infants have been poorly studied. MATERIALS AND METHODS: Lung volume, SpO2, perfusion index, regional SO2, transcutaneous partial pressure of CO2 were simultaneously monitored and recorded ten minutes after surfactant tracheal instillation in elective HFOV ventilated preterm infants with RDS. OUTCOMES: Despite a reduction in gas exchange during the first 5 minutes post surfactant instillation, most likely dependent on airway obstruction, lung volume increases rapidly in HFOV preterm infants with RDS. After 5 minutes from administration of surfactant, lung volume, gas exchange and PI reach stable values and CDP can be safely reduced.

Neurologic assessment tool for screening preterm infants at term age.

The screening assessment tool of the Dubowitz neonatal neurologic assessment was adapted for preterm infants. The findings identified as "warning signs" in preterm infants were identical to those found in full-term infants, suggesting that this screening tool can also be used in preterm infants at term age.

Platelet reactivity and endothelial function in children of patients with early acute myocardial infarction.

AIMS: To assess whether platelet reactivity is increased in offspring of patients with early acute myocardial infarction (AMI) and its possible relation with endothelial dysfunction. METHODS AND RESULTS: We studied 23 healthy children (15±3 years, 13 males) of patients with early AMI (≤50 years old; Group 1) and 21 healthy children of healthy subjects without any history of cardiovascular disease (14±3 years, 10 males; Group 2). Platelet reactivity was assessed by flow cytometry as the increase in monocyte-platelet aggregates (MPA) and CD41 and PAC-1 platelet expression in response to exercise stress test (EST), adenosine diphosphate (ADP) stimulation (10(-7) M), or both. Endothelial function was assessed by measuring brachial artery dilation during post-ischaemic forearm hyperaemia [flow-mediated dilation (FMD)]. Both EST and ADP induced a higher percentage increase in platelet receptor expression in Group 1, compared with Group 2, with the most significant difference being shown for the response to the combined stimuli (e.g. MPA, 23.1±12 vs. 5.63±8%, P<0.001; platelet PAC-1, 57.7±47 vs. 13.2±7%, P<0.001). Compared with Group 2, Group 1 children showed lower FMD (10.7±3.1 vs. 8.0±2.9%, respectively; P=0.007). However, no significant association was found between FMD and platelet reactivity. CONCLUSION: Our results show increased platelet reactivity in children of patients with early AMI; the finding was not significantly correlated with endothelial dysfunction, suggesting that other mechanisms are mainly involved in the enhanced platelet response to agonistic stimuli.

Use of a combined SpO2/PtcCO2 sensor in the delivery room.

Arterial oxygen saturation (SaO(2)) and partial arterial pressure of carbon dioxide (PaCO(2)) are important respiratory parameters in critically ill neonates. A sensor combining a pulse oximeter with the Stow-Severinghaus electrode, required for the measurement of peripheral oxygen saturation (SpO(2)) and transcutaneous partial pressure of carbon dioxide (PtcCO(2)), respectively, has been recently used in neonatal clinical practice (TOSCA(500Ò)Radiometer). We evaluated TOSCA usability and reliability in the delivery room (DR), throughout three different periods, on term, late-preterm, and preterm neonates. During the first period (period A), 30 healthy term neonates were simultaneously monitored with both TOSCA and a MASIMO pulse oximeter. During the second period (period B), 10 healthy late-preterm neonates were monitored with both TOSCA and a transcutaneous device measuring PtcCO(2) (TINA(Ò) TCM3, Radiometer). During the third period (period C), 15 preterm neonates were monitored with TOSCA and MASIMO after birth, during stabilization, and during transport to the neonatal intensive care unit (NICU). Blood gas analyses were performed to compare transcutaneous and blood gas values. TOSCA resulted easily and safely usable in the DR, allowing reliable noninvasive SaO(2) estimation. Since PtcCO(2) measurements with TOSCA required at least 10 min to be stable and reliable, this parameter was not useful during the early resuscitation immediately after birth. Moreover, PtcCO(2) levels were less precise if compared to the conventional transcutaneous monitoring. However, PtcCO(2) measurement by TOSCA was useful as trend-monitoring after stabilization and during transport to NICU.

Renal failure of the surviving fetus after intrauterine death of the co-twin.

Twin pregnancies are considered at a higher risk for fetal mortality than singleton pregnancies. The antenatal death of one of the twins is associated with an increasing rate of cerebral impairment and lesions in other organs in the surviving fetus, especially if the pregnancy is monochorionic. We describe a case of isolate renal failure becoming evident gradually after birth in a surviving twin after the antenatal death of the co-twin. Considering the deleterious effects of vascular disruption in a surviving twin, our findings suggest careful investigation of renal function, even if no intrauterine signs of diminished renal function were previously detected.

Electrical and autonomic cardiac function in patients with Dravet syndrome.

Dravet syndrome (DS) is an epileptic encephalopathy related mainly to mutations in the SCN1A gene, encoding for neuronal sodium channels. Patients with DS have a high risk of sudden unexpected death in epilepsy (SUDEP). In this study we investigated whether patients with DS present abnormalities in electrical and autonomic cardiac function. To this aim we assessed ventricular repolarization and heart rate variability (HRV) on standard electrocardiography (ECG) and on 24-h ECG Holter monitoring, respectively, in 20 patients affected by DS (6.8 ± 4 years, 11 female). As age- and sex-matched control groups, we also studied 20 patients with other epileptic syndromes receiving antiepileptic drugs (ES/AED, 6.0 ± 5 years, 12 female), 20 patients with other epileptic syndromes without treatment (ES/no-AED, 6.7 ± 4 years, 10 female), and 20 healthy children (HC, 7.2 ± 5 years, 11 females). Data analysis showed that patients with DS had depressed HRV variables compared to both ES patients (ES/AED and ES/no-AED) and HC control group, whereas no significant differences in HRV variables were found between ES patients (with and without treatment) and HC. There was no significant difference between patients with DS and all the other control groups in RR intervals, QT, and QTc interval analysis. In conclusion, DS patients display an imbalance of cardiac autonomic function toward a relative predominance of adrenergic tone compared to both healthy children and patients with other forms of epilepsy, independent of antiepileptic therapy. Follow-up studies should clarify the clinical significance of this autonomic impairment and whether HRV analysis can be helpful in predicting the risk of sudden death in patients with DS.

Is growth-discordance in twins a substantial risk factor in adverse neonatal outcomes?

To evaluate whether growth discordance is an independent risk factor in the neonatal outcome of the smaller twin, all medical records of twin pregnancies delivered between 26 and 41 weeks during a 5-year period (January 2004-December 2008) were reviewed. Among the 49 selected twins, weight discordance was 15-20% in 7 infants, 21-30% in 16 infants, 31-40% in 16 infants and > 40% in 10 infants. No significant differences between the four groups were found with regards to obstetric complications and neonatal disease. Occurrence of birthweight below the 10th percentile and rate of admission to the neonatal intensive care unit significantly increased as intra-pair birthweight difference increased (p = .03). The > 40% discordant group had a significantly lower gestational age (p = .03), lower birthweight (p = .007) and a significantly higher mortality rate (4/10 versus 3/39 p = .04) in comparison with the other discordant groups. Multiple logistic regression analysis showed that birthweight was the single independent and consistent factor associated with elevated risks of mortality. For every 250 g increase in birthweight, the risk for mortality decreased by about 84% [RR 0.16(CI 0.00-0.70)]. Gestational age was the most reliable predictor for major neonatal complications. For every 1-week increase in gestational age a significant decreased risk for all outcomes was found. Discordance alone should not be considered as a predictor for adverse neonatal outcome. Neonatal outcome in discordant twins appears to be related to gestational age and birthweight rather than to the degree of discordance.

Current Italian practices regarding the management of hyperbilirubinaemia in preterm infants.

AIM: To assess the current practices existing in Italy for the management of jaundice in preterm infants as preliminary achievement to a call for national guidelines and establishment of a kernicterus registry. METHODS: A questionnaire (in Supporting Information online) was sent to the 109 level III neonatal units in Italy to ascertain existing guidelines for total bilirubin monitoring and treatment of hyperbilirubinaemia in preterm infants and occurrence of kernicterus. RESULTS: There was a 61% (67/109) response rate. Eighty-five per cent of responding units had either written guidelines coming from different literature sources or locally developed. The monitoring of bilirubin varied greatly in timing before, during and after jaundice development. Phototherapy and exchange transfusion were given to 56.0 ± 21.0% and 0.2 ± 0.4% of admitted preterm infants in participating centres. Five cases of kernicterus in preterm infants and eleven cases in term infants were documented over the last 10 years. CONCLUSION: The management of hyperbilirubinaemia in preterm infants is not uniform in Italy and would benefit from shared national guidance together with establishment of a kernicterus registry to guide therapy.