[The Outpatient Health Care Package for the very premature infant: application of the program to follow-up services for the Neonatal Intensive Care, Pediatrics Department, Università "La Sapienza" I Facoltà, Roma (June 2008-March 2010)]. / II Pacchetto Ambulatoriale Complesso (PAC) del neonato altamente pretermine: applicazione del programma presso il servizio di follow-up della Terapia Intensiva Neonatale, Dipartimento di pediatria, Università "La Sapienza" I Facoltà, Roma (Giugno 2008-Marzo 2010).

Fifty-nine children were enrolled in the Outpatient Health Care Package (OHCP) from 01/06/2008 to 31/03/2010. All children, except two, attended entirely the follow-up appointments; a satisfactory result, considering also that 30% of family were living outside the urban area and more than a third of the families was originated in a foreign country. At 3 months corrected age(CA) Haemoglobin mean values of 47 infants, all in iron treatment, were: 12.26 (10.1-14-1) g/dL; 25% had values between 10.1 and 12 g/dL. Mean values for Calcium were 10.75 (9.50-15.26) mg/dL Mean values for ALP were 393 (179-1075) UI/L, values >1000 UI/L were found in two infants who suspended Vitamin D treatment. At 3 months CA 50 infants performed ABR, 12 of these showing abnormalities. To date 9 infants repeated ABR at 6-9 months CA, 4 of these showed again abnormal results. Overall were found 4 ABR abnormalities among 47 children (8.5%). Outcome of 23 children at 12 months CA: no moderate or severe neurologic abnormalities were found, 4 children (17.4%) presented mild abnormalities, 2 were referred for rehabilitation. No QSM <80% was found (mean QSM 93.7%) in 10 children evaluated. One child presented growth retardation <5 degrees; 2 underwent laser treatment for ROP with normal vision, 7 (30.4%)had sistolic BP > or = 95 degrees; 6 (26%) were rehospitalized. This experience was positive: OHCP promoted a better compliance and standardization of follow-up. It would be desirable to prolong OHCP until school-age, including renal and cardiac functions monitoring.

Pathogenesis of apparent life-threatening events in infants with esophageal atresia.

Many infants with a repaired esophageal atresia (EA) undergo fundoplication, aortopexy, or glossopexy because the mechanisms most responsible for airway obstruction and/or apparent life-threatening event (AO/ALTE) syndrome are considered to be gastroesophageal reflux (GER), tracheal compression (TC), or obstructive apnea, respectively. In the present study, we investigated whether these mechanisms are independent or interrelated. We developed a database of 120 consecutive patients with EA treated by the senior author between 1967-2002. We studied the clinical manifestations of patients with a cervical esophagostomy and/or blind lower esophageal stump, which ruled out TC and/or proximal esophageal GER as a mechanism for AO/ALTE. Of 25 neonates who underwent section/ligation of lower tracheo-esophageal fistula and/or feeding gastrostomy, 10 critically ill neonates died. Of 15 survivors, 9 infants had a feeding gastrostomy without an esophagostomy. Of these, 6 infants presented one or more episodes of AO, and 8 presented ALTE with or without AO. Subsequently, 5 of the 9 infants underwent an esophagostomy. Eventually, 11 infants had a feeding gastrostomy with an esophagostomy. Of the latter, 5 infants presented one or more episodes of AO, and 6 presented ALTE without AO. In conclusion, oral feeding, proximal esophageal GER, and TC are not essential for AO/ALTE syndrome to occur. They are probably factors which offer evidence of an underlying problem with control of upper airway patency.

Circulating thrombopoietin levels in neonates with infection.

Thrombocytopenia is a commonly encountered hematologic complication in neonates with sepsis. Thrombopoietin (TPO) is the principal physiologic regulator of megakariocytopoiesis and platelet production. This study was carried out to determine whether variations in circulating TPO levels would occur in infected neonates and/or if they would correlate with platelet counts. In a prospective study of 36 sick neonates (gestational age 24-42 wk) admitted to a regional Neonatal Intensive Care Unit (NICU), blood was collected for TPO measurements and platelet counts on admission to the NICU, if infection was inferred, and at recovery before discharge. An additional group of 15 apparently healthy neonates was also studied (median postnatal age at the time of blood sampling for TPO assessment: 4 d, range 1-10) as control. TPO was measured on plasma samples using a commercially available enzyme-immunosorbent assay (ELISA). On admission, the majority (21/36) of the sick neonates had non-infectious diseases, 2 had early onset sepsis, and 13 had infection (defined as the presence of clinical signs of sepsis, abnormal leukocyte counts or C-reactive protein values, and positive results on local cultures, but negative blood culture results). During the hospital stay, 5 neonates developed sepsis (positive blood culture) and 6 had infection (as previously defined) or necrotizing enterocolitis (NEC). The median TPO level (1704 pg/ml, range 51-3912) was higher during sepsis (either early or late) than during infection (included NEC) (198 pg/ml, range 21-2504), or non-infectious disease (659 pg/ml, range 0-2533), while platelet counts (median value 37,000 cells/microl, range 15,000-486,000) were lower than during either infection (included NEC) (median value 238,000 cells/microl, range 49,000-655,000) or non-infectious disease (median value 110,000 cells/microl, range 45,000-549,000). When infants had recovered from these illnesses, TPO concentrations markedly dropped (median value 59 pg/ml, range 0-825). These values were similar to those found in the control neonates (median TPO level 85 pg/ml, range 43-620). In infected neonates (sepsis plus infection), TPO levels inversely correlated with platelet counts (r = -0.634, p = 0.001) as did those of infants with non-infectious disease (r = -0.574, p = 0.006), while there was no significant correlation between TPO levels and platelet counts in the samples obtained after recovery or in the control infants. We conclude that infected neonates have high circulating TPO levels in the face of low platelet counts. Whether larger TPO concentrations following exogenous administration of recombinant TPO would restore the number of circulating platelets warrants further investigation.

Clinical approach to the analysis of causes of death in the first two years of life of very-low-birthweight infants in a multicentre setting.

Mortality in the first 2 years of 634 very-low-birthweight infants admitted to eight neonatal intensive care units in Italy, and the factors associated with the net probability of death from each cause, were studied by means of the Cox proportional hazard model. A clinical classification of the causes of death was used. Overall mortality was 33.7% (intercentre range 12.6-52.9%). The highest cause-specific mortality rates were observed for respiratory problems, intra-ventricular haemorrhage (IVH) and infections (14.5%, 6.3% and 5.7% respectively). The leading causes of death were respiratory problems and IVH in the first week of life, infections from the second week up to the end of the first month, and bronchopulmonary dysplasia (BPD) afterwards. Birthweight < 1000 g, gestational age < 30 weeks, absence of spontaneous respiratory activity, unknown body temperature and pH < 7.20 at admission were associated with death from respiratory problems and IVH. Male sex, birthweight < 1000 g and unknown body temperature at admission were associated with death from BPD. Mortality from infections was higher in one centre; no other differences emerged among the eight NICUs. The classification of the causes of death employed and the use of the net probabilities of death appear as practical and useful instruments to study the relationship between specific aspects of medical care and mortality, and to investigate the reasons for differences in performance between neonatal units.

Care procedures in the healthy full-term newborn infant: a territorial survey.

The Italian Academy of Pediatrics and the Italian Academy of Neonatology have carried out an investigation regarding assistance routines for the healthy full-term newborn. The results confirm a need for modifications in the majority of the centers, especially with regard to Vitamin K prophylaxis which is implemented with extremely variable dosages and not repeated, and to breast-feeding and rooming-in, both of which should be more encouraged. The length of stay in hospital for both vaginal and cesarean deliveries, especially in Lazio, is excessive. Regarding ocular prophylaxis and allergic disease prophylaxis, the attitude is uniform and in agreement with recent literature.

[Characteristics of airway colonization in mechanically ventilated newborn infants]. / Le caratteristiche della colonizzazione delle vie aeree nel neonato ventilato meccanicamente.

This study was designed to define the pattern of airway colonization in mechanically ventilated neonates and to assess whether this is associated with clinical signs of infection and/or local or systemic inflammation. One hundred and fifty-seven bronchoalveolar lavages (BAL) were obtained from 40 intubated neonates for microbiologic and cytologic evaluation of the distal airway. Concomitantly with each BAL, clinical data and laboratory tests were recorded. Ninety-seven BAL were negative, whilst 56 (37%) yielded the growth of gram-positive bacteria (84%), gram-negative bacteria (6%), fungi (5%), or P. carinii (5%). Airway colonization occurred in 9 (22%) neonates within the first 72 hours of life and in 31 (78%) during the following days. S. aureus was the most commonly isolated organism (70%). Clinical signs of pulmonary infection were present in all cases of vertical colonization and in 35 (66%) of nosocomial transmission. Blood and BAL white cell counts were higher coincidentally with airway colonization (p = 0.13 and p = 0.57, respectively). Antibiotic treatment was changed on the basis of BAL culture results. Follow-up cultures of the BAL were obtained in 13 neonates in whom antibiotics were changed. Negative cultures were found in 8 of these neonates, and 50% of these cases showed clinical improvement. Further work is needed to assess the cost-benefit ratio of prophylactic antibiotic administration in intubated neonates and the possible advantage(s) of treating microorganisms colonizing the airway of these subjects.

[Purpura fulminans in the newborn. Report of two cases successfully treated with heparin and antithrombin III]. / La purpura fulminans nel neonato. Descrizione di due casi trattati efficacemente con eparina ed antitrombina III.

Purpura fulminans is a rare form of disseminated intravascular coagulation characterized by rapidly progressive purpuric lesions, hypotension and, in some cases, fever. In neonates, purpura fulminans usually develops following deficiency of anticoagulant protein C or S, although acquired forms have been described. The management of disseminated intravascular coagulation is still controversial, with some studies finding a positive effect of anticoagulants and others showing no effect or even a detrimental one. Therefore, at present, management is limited to the treatment of underlying disease and replacement of clotting factors. Personal experience is reported on the efficacy of heparin in combination with antithrombin III in the treatment of purpura fulminans in two preterm neonates who did not have inherited deficiency of protein C or S and developed the disease possibly following prolonged labor (36 hours) in the first case, and maternal neoplasia, in the second. Both neonates presented with widespread cyanotic areas rapidly evolving in purpuric lesions and hemorrhagic bullae. Laboratory tests (prolonged prothrombin and partial thromboplastin time, fibrinogen and antithrombin III concentrations below normal ranges, d-dimer highly positive) were consistent with disseminated intravascular coagulation. In both cases anticoagulant treatment with heparin (50 UI/kg in bolus followed by 15 UI/kg/h) and antithrombin III was associated with resolution of disseminated intravascular coagulation and prompt amelioration of the purpuric lesions, without apparent side effects.

Chlamydia trachomatis-associated respiratory disease in the very early neonatal period.

Of 103 preterm neonates admitted consecutively to the neonatal intensive care unit soon after birth for respiratory distress, 8 were found to be Chlamydia trachomatis-positive as early as within the first 24 h of life. All these patients required mechanical ventilation and supplemental oxygen. Six infants had evidence on chest radiographs of hyaline membrane disease, one of pneumonia, and one of slight bilateral parenchymal changes. Our results suggest that the presence of C. trachomatis in preterm infants with neonatal respiratory distress is probably not an infrequent event.

Italian multicentre study on very low-birth-weight babies. Neonatal mortality and two-year outcome.

The Italian multicentre study on very low-birth-weight babies is the first collaborative project in Italy on the health status of newborns weighing 500-1499 g at birth: 634 such babies were admitted in 1987-88 to eight Italian NICUs; 424 infants survived and were followed until two years of age, corrected for prematurity. Logistic regression analysis of pre-admission risk factors of in-hospital mortality identified eight statistically significant variables: birth weight, gestational age, sex, antepartum steroids, 1-min Apgar score and, on admission to the NICU, body temperature, pH and absence of spontaneous respiration. Using the equation derived from the logistic model, a theoretical mortality rate was calculated for each centre, predicted on the basis of the local incidence of preadmission risk factors. In no case was the predicted mortality significantly different from the observed one. At two years of age, 8 children were blind and 48 had motor disability. Of these, 46 had cerebral palsy: based on a functional evaluation score 14 had severe (degree 4), 20 intermediate (degree 3) and 12 mild cerebral palsy (degree 2). Among 25 variables entered in a logistic regression as risk factors for cerebral palsy, only periventricular leukomalacia and acidosis were significantly associated with the outcome.

[Mortality and care level of very low birth weight newborn infants. A population study]. / Mortalità e livello delle cure in neonati di peso molto basso. Uno studio di popolazione.

A population study on 314 very low birth weight infants (VLBW) was carried out in 1987 in the Lazio Region of Italy to investigate the relation between the availability at birth of neonatal intensive care and infant mortality. Fifty-two percent of VLBW infants did not survive the first year of life. The mortality Odds Ratios, adjusted for four potential confounding variables, did not show a beneficial effect of Maternity units with neonatal intensive care (level 3) compared with those with special (level 2) and normal care (level 1). The overall high crude mortality rate together with the homogeneity of odds ratios among the different levels of care suggest that, when a regionalized perinatal care system is missing, as in Lazio region, the availability of neonatal intensive care, per se, does not improve the survival on this group of infants.

Italian Multicenter Study on Very Low Birth Weight Babies.

The Italian Multicenter Study on Very Low Birth Weight babies (IMS-VLBW) is the first collaborative investigation performed in Italy on the health status of newborns weighing less than 1500 g at birth. Eight Neonatal Intensive Care Units (NICUs) participated in the study: Cagliari, Napoli, Padova, Palermo, Roma, Sassari, Trieste, Udine. Data were analyzed in the Laboratorio di Epidemiologia e Biostatistica of the Istituto Superiore di Sanità. The objectives of the study were established in the following: a) to collect accurate descriptive data on neonatal morbidity, mortality and long term outcome of VLBW babies admitted to NICUs; b) to analyze the risk factors of unfavourable outcome (death or handicap) and to analyze, with respect to outcome, the relationships between risk factors, neonatal diseases and therapeutical procedures; c) to test the feasibility of a multicenter follow-up programme based on the use in all participating Centers of the same diagnostic criteria (the results of follow-up will be presented in a forthcoming paper). In the years 1987 and 1988, 634 newborns weighing 500-1499 g at birth were enrolled in the study. In-hospital mortality for the whole group was 33.1% (65.1% in the 500-999 g birth weight class and 19.2% in the 1000-1499 g class). Mortality was not different for inborn vs outborn babies. A high incidence of unfavourable perinatal conditions was observed in these babies, namely birth asphyxia, sub-optimal care during transport, poor clinical conditions on arrival to the NICU. Neonatal diseases, like respiratory distress syndrome and peri-intra ventricular hemorrhage were also frequent and severe. A logistic regression analysis of pre-admission risk factors of in-hospital death identified eight statistically significant variables: birth weight; gestational age; sex; antenatal steroid stimulation of lung maturity; first minute Apgar score; absence of spontaneous respiration, body temperature and pH on arrival to the NICU. Using the equation derived from the logistic regression analysis a theoretical mortality rate, predicted on the basis of the local incidence of pre-admission risk factors, was calculated for each Center. In no case the predicted mortality was statistically different from the observed one, suggesting that in our study differences in observed mortality rates from one Center to another are largely influenced by pre-admission risk factors.

Immunologic follow-up of infants treated with granulocyte transfusion for neonatal sepsis.

The immunologic status and the occurrence of alloimmunization against granulocytes, platelets, lymphocytes, and red cells was evaluated in 33 babies who received granulocyte transfusion because of neonatal sepsis. Nine age-matched babies were examined as control. A first group of 19 infants was examined only once between 6 and 23 months of age. Alloantibodies were searched by the following serologic methods: standard techniques for red cell antibodies; lymphocytotoxicity test; agglutination and immunofluorescence tests on granulocytes and platelets. No antibodies were demonstrated. The immunologic profile was investigated by determining the Ig levels, the percentage of E rosette-forming cells, and the lymphocyte blastic response to phytohemagglutinin and concanavalin A. Granulocyte function was studied by phagocytosis and killing of Candida. No significant differences were observed between treated and control babies. In a second group of 14 infants the occurrence of early immunization within 3 to 9 weeks after the last transfusion was investigated. No evidence of early immunization was found. The present data suggest that following neonatal granulocyte transfusion the risk of adverse immune reactions should be low.

Vitamin D-binding protein in the perinatal period.

The molecular polymorphism and quantitative levels of serum vitamin D-binding protein (DBP) were ascertained in a group of preterm, full-term and hypocalcaemic full-term newborn infants. The serum concentration of DBP is not influenced by phenotype and increases with fetal age from the 32nd-33rd week of gestation until the 35th week of gestation. Neither different DBP allele distribution nor abnormal quantitative levels found among 29 hypocalcaemic full-term newborn infants.

Transferrin C subtypes in extremely premature newborn infants.

Genetic typing of serum transferrin was performed in a group of 88 extremely premature infants (gestation age less than 32 wk) and in a control group of 351 full-term infants, using isoelectric focusing technique on ultrathin layer of polyacrilamide gel. A major incidence of C2 type was found among the preterm infants when compared to full-term infants X2 = 22,86, (P less than 0.001). In view of the previously reported higher incidence of this phenotype in women prone to spontaneous abortion, a selective mechanism associated with this serum transferrin type promoting spontaneous abortion and preterm delivery, seems to occur. The relative risk of preterm delivery were calculated to 1.4 and 8.3 for the C2-1 and C2 types, respectively. Supportive evidence in favour of this hypothesis is offered by the correlation existing between transferrin C2 allele and placental alkaline phosphatase variant F, the latter being associated with increased risk of spontaneous abortion.

Critical vitamins for low birthweight infants.

All vitamins are "critical" by definition for the growing infant. However, some of them are particularly relevant to the preterm or low birthweight (LBW) infant in whom a deficiency can occur more frequently than in a full-term newborn. In LBW infants vitamin deficiency may develop due to (1) low body stores at birth, (2) low intake, (3) limited absorption, (4) increased need or utilization, (5) presence of certain clinical conditions. The first reason concerns all lipid-soluble vitamins, and particularly vitamin E and K, which cross the placenta with some difficulty. Among hydrosoluble vitamins, cord-blood levels of vitamin B6 have been shown to be abnormally low in preterm infants. Low intake can occur because of low vitamin levels in milk or because of delayed and/or insufficient feeding. Limited intestinal absorption of vitamins in LBW infants has only been demonstrated for vitamin E and folic acid. The rapid post-natal growth may lead to increased vitamin utilization. In some clinical conditions particularly high intakes of certain vitamins are indicated. In our opinion, the really "critical" vitamins in LBW infants are vitamin D, E, K and folic acid, for which routine supplementation can be recommended, and possibly vitamins C and B6 under special circumstances.

Prolonged intermittent positive pressure ventilation by nasal prongs in intractable apnea of prematurity.

In order to avoid endotracheal intubation in very small newborn infants requiring prolonged intermittent positive pressure ventilation (IPPV), a method was developed allowing delivery of IPPV by means of nasal prongs (nasal IPPV). A series of 10 newborn infants weighing 1 200 g or less, and requiring nasal IPPV for 5 to 14 days because of intractable apnea has been reported. Five infants survived. With the exception of hearing defects in two survivors, no lesions possibly due to the ventilation procedure were observed. Follow-up examination showed severe mental and motor handicap in one infant, and apparently normal mental and motor development in 3 infants examined at the age of 12-27 months. It is suggested that nasal IPPV is an effective and safe method for prolonged ventilation of very small newborn infants with normal or not severely affected lungs, whereas it appears of very limited use in patients with stiff lungs, such as in severe HMD.

[Echocardiography for the evaluation of tricuspid atresia. I. Morphological analysis (author's transl)]. / Valutazione dell'atresia della tricuspide mediante ecocardiografia. I) Analisi morfologica.

Twenty-five patients with tricuspid atresia, ranging in age between 3 months and 23 years, were studied by M-mode and two-dimensional (2D) echocardiography. In all of them diagnosis was confirmed by cardiac catheterization and angiocardiography and in most of them at surgery or autopsy. Some anatomical specimens of tricuspid atresia were analyzed in order to be correlated with corresponding two-dimensional pictures. Contrast 2D echocardiography was performed in 12 of 25 patients. M-mode scanning right atrium-left ventricle showed a rudimentary echo coming from the atretic valve but didn't show its relations with the membranous portion of ventricular septum. 2D echocardiography in (two chambers) or (four chambers) view was particularly useful to distinguish tricuspid atresia from other hypoplastic right heart syndromes with functioning tricuspid valve. Peripheral contrast injection enhances diagnostic capability of 2D echocardiography, especially for the assessment of right ventricular dimensions, differentiation between atretic and imperforate valve and evaluation of ventricular septal defect.