Neurodevelopmental outcome of Italian preterm ELBW infants: an eleven years single center cohort.

BACKGROUND: Preterm extremely low birth weight infants (ELBWi) are known to be at greater risk of developing neuropsychiatric diseases. Identifying early predictors of outcome is essential to refer patients for early intervention. Few studies have investigated neurodevelopmental outcomes in Italian ELBWi. This study aims to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year single-center cohort of Italian ELBWi and to identify early risk factors for adverse neurodevelopmental outcomes. METHODS: All infants born with birth weight < 1000 g and admitted to the Neonatal Intensive Care Unit of the "Fondazione IRCCS Policlinico San Matteo" hospital in Pavia, Italy, from Jan 1, 2005 to Dec 31, 2015 were eligible for inclusion. At 24 months, Griffiths' Mental Developmental Scales Extended Revised (GMDS-ER) were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). Univariate and multivariate multinomial logistic regression models were performed to analyze the correlation between neonatal variables and neurodevelopmental outcome. RESULTS: 176 ELBWi were enrolled (mean gestational age 26.52 weeks sd2.23; mean birthweight 777.45 g sd142.89). 67% showed a normal outcome at 24 months, 17% minor sequelae and 16% major sequelae (4.6% cerebral palsy on overall sample). The most frequent major sequela was cognitive impairment (8.52%). In the entire sample the median score on the Hearing-Speech subscale was lower than the median scores recorded on the other subscales and showed a significantly weaker correlation to each of the other subscales of the GMDS-ER. Severely abnormal cUS findings (RRR 10.22 p 0.043) and bronchopulmonary dysplasia (RRR 4.36 p 0.008) were independent risk factors for major sequelae and bronchopulmonary dysplasia for minor sequelae (RRR 3.00 p 0.018) on multivariate multinomial logistic regression. CONCLUSIONS: This study showed an improvement in ELBWI survival rate without neurodevelopmental impairment at 24 months compared to previously reported international cohorts. Cognitive impairment was the most frequent major sequela. Median scores on GMDS-ER showed a peculiar developmental profile characterized by a selective deficit in the language domain. Severely abnormal cUS findings and bronchopulmonary dysplasia were confirmed as independent risk factors for major sequelae.

Neurodevelopmental outcome of preterm very low birth weight infants admitted to an Italian tertiary center over an 11-year period.

Preterm very low birth weight infants (VLBWi) are known to be at greater risk of adverse neurodevelopmental outcome. Identifying early factors associated with outcome is essential in order to refer patients for early intervention. Few studies have investigated neurodevelopmental outcome in Italian VLBWi. The aim of our longitudinal study is to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year cohort of 502 Italian preterm VLBWi and to identify associations with outcome. At 24 months, Griffiths' Mental Developmental Scales were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). 75.3% showed a normal outcome, 13.9% minor sequelae and 10.8% major sequelae (3.8% cerebral palsy). Male gender, bronchopulmonary dysplasia, abnormal neonatal neurological assessment and severe brain ultrasound abnormalities were independently associated with poor outcome on multivariate ordered logistic regression. Rates of major sequelae are in line with international studies, as is the prevalence of developmental delay over cerebral palsy. Analysis of perinatal complications and the combination of close cUS monitoring and neurological assessment are still essential for early identification of infants with adverse outcome.

Placental features of fetal vascular malperfusion and infant neurodevelopmental outcomes at 2 years of age in severe fetal growth restriction.

BACKGROUND: Placental pathologic lesions suggesting maternal or fetal vascular malperfusion are common among pregnancies complicated by intrauterine growth restriction. Data on the relationship between pathologic placental lesions and subsequent infant neurodevelopmental outcomes are limited. OBJECTIVE: This study aimed to assess the relationship between placental pathologic lesions and infant neurodevelopmental outcomes at 2 years of age in a cohort of pregnancies complicated by intrauterine growth restriction. STUDY DESIGN: An observational cohort study included singleton intrauterine growth restriction pregnancies delivered at ≤34 weeks' gestation and with a birthweight of ≤1500 g at a single institution in the period between 2007 and 2016. Maternal and neonatal data were collected at discharge from the hospital. Infant neurodevelopmental assessment was performed every 3 months during the first year of life and every 6 months in the second year. Penalized logistic regression was used to test the association of maternal vascular malperfusion and fetal vascular malperfusion with infant outcomes adjusting for confounders. RESULTS: Of the 249 pregnancies enrolled, neonatal mortality was 8.8% (22 of 249). Severe and overall maternal vascular malperfusion were 16.1% (40 of 249) and 31.7% (79 of 249), respectively. Severe maternal vascular malperfusion was associated with an increased risk of neonatal mortality (adjusted odds ratio, 3.3; 95% confidence interval, 1.2-9.5). Among the 198 survivors after a 2-year neurodevelopmental follow-up evaluation, the rate of major and minor neurodevelopmental sequelae was 57.1% (4 of 7) among severe fetal vascular malperfusion (adjusted odds ratio, 24.5; 95% confidence interval, 4.1-146), 44.8% (13 of 29) among overall fetal vascular malperfusion (adjusted odds ratio, 5.8; 95% confidence interval, 5.1-16.2), and 7.1% (12 of 169) in pregnancies without fetal vascular malperfusion. Infants born from pregnancies with fetal vascular malperfusion also had lower 2-year general quotient, personal-social, hearing and speech, and performance subscales scores than those without fetal vascular malperfusion. Finally, in the presence of fetal vascular malperfusion, the likelihood of a 2-year infant survival with normal neurodevelopmental outcomes was reduced by more than 70% (adjusted odds ratio, 0.29; 95% confidence interval, 0.14-0.63). Noticeably, 10 of the 20 subjects with a 2-year major neurodevelopmental impairment (3 of 4 with severe fetal vascular malperfusion) had little or no abnormal neurologic findings at discharge from neonatal intensive care unit. CONCLUSION: In preterm intrauterine growth restriction, placental fetal vascular malperfusion is correlated with an increased risk of abnormal infant neurodevelopmental outcomes at 2 years of age even in the absence of brain lesions or neurologic abnormalities at discharge from the neonatal intensive care unit. In the case of a diagnosis of fetal vascular malperfusion, pediatricians and neurologists should be alerted to an increased risk of subsequent infant neurodevelopmental problems.

Literature Review and an Italian Hospital Experience about Post-Natal CMV Infection Acquired by Breast-Feeding in Very Low and/or Extremely Low Birth Weight Infants.

Breastfeeding is recommended for all neonates due to a known variety of beneficial effects, but infants can be infected by cell-associated bacteria and viruses from breast milk, such as cytomegalovirus (CMV). The majority of CMV-seropositive breastfeeding women have a viral, self-restricted reactivation, can shed the virus in the milk for about 12 weeks after delivery, and can transmit the infection to their offspring. Post-natal CMV-infected term infants are mainly asymptomatic, while very low birth weight (VLBW, <1500 g) and extremely low birth weight (ELBW, <1000 g) infants may present with severe disease, short-term sequelae ranging from abnormalities in laboratory indexes to sepsis-like syndrome, and long-term sequelae such as developmental problems. Thus, the use of thermally treated maternal milk for VLBW/ELBW infants may be indicated to prevent/reduce the risk of CMV transmission. Different techniques, with varying efficacy in eradicating CMV and maintaining the activity of biological compounds in milk are available: long/short pasteurization, freeze-thawing, the use of microwaves, and ultraviolet-C irradiation. In our NICU, the use of maternal raw milk is always strongly recommended for term/preterm infants, but to reduce risk of CMV transmission, freeze-thawing mother's own milk is used in neonates with GA ≤ 30 weeks or/and weight ≤ 1000 g, usually regardless of serological maternal condition, as CMV screening is not routinely offered to pregnant women and the milk of seroimmune mothers is not evaluated for CMV reactivation, as its rate is similar to seroprevalence. Over the last 4 years, we had 10 VLBW/ELBW newborns in our NICU with late-onset sepsis and negative cultures. In these cases, the research of CMV DNA in neonatal urine or saliva, for the diagnosis of post-natal symptomatic infection (once congenital transmission has been excluded) may be useful and not invasive. The take-home message we would like to share is that acquired CMV infection should be considered in VLBW/ELBW infants breastfed by seropositive mothers and presenting severe symptoms-particularly sepsis with negative cultures. This could allow pediatricians to make better-quality diagnoses, perform supportive therapy, provide antiviral treatment if needed, or establish a "pre-emptive" therapy for these high-risk neonates.

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform.

We analyzed by next-generation sequencing (NGS) 67 epilepsy genes in 19 patients with different types of either isolated or syndromic epileptic disorders and in 15 controls to investigate whether a quick and cheap molecular diagnosis could be provided. The average number of nonsynonymous and splice site mutations per subject was similar in the two cohorts indicating that, even with relatively small targeted platforms, finding the disease gene is not an univocal process. Our diagnostic yield was 47% with nine cases in which we identified a very likely causative mutation. In most of them no interpretation would have been possible in absence of detailed phenotype and familial information. Seven out of 19 patients had a phenotype suggesting the involvement of a specific gene. Disease-causing mutations were found in six of these cases. Among the remaining patients, we could find a probably causative mutation only in three. None of the genes affected in the latter cases had been suspected a priori. Our protocol requires 8-10 weeks including the investigation of the parents with a cost per patient comparable to sequencing of 1-2 medium-to-large-sized genes by conventional techniques. The platform we used, although providing much less information than whole-exome or whole-genome sequencing, has the advantage that can also be run on 'benchtop' sequencers combining rapid turnaround times with higher manageability.

Neurodevelopmental outcome of preterm very low birth weight infants born from 2005 to 2007.

OBJECTIVE: To evaluate short-term neurodevelopmental outcome (at 24 months of corrected age) and correlations with obstetric and neonatal factors in a sample of preterm very low birth weight infants born and admitted to an Italian tertiary centre between 2005 and 2007. METHODS: 156 infants with a birth weight ≤ 1500 g (gestational age, range: 27-31 weeks) were followed at regular intervals through neurodevelopmental (neurological and psychomotor) assessment up to 24 months of corrected age. A statistical analysis was conducted in order to look for correlations between pre- and perinatal variables and neuropsychomotor outcome at 24 months. RESULTS: 131 children were classified as normal and the other 25 presented sequelae classified as "minor" in 17 cases and as "major" in eight. The most significant risk factors for a poor outcome were preterm premature rupture of the membranes, bronchodysplasia, late-onset sepsis, postnatal steroid therapy and male gender. The presence of severe abnormalities on brain ultrasound scan and of an abnormal neurological assessment at 40 weeks at term equivalent age were strong predictors of poor outcome. CONCLUSIONS: Our study is one of the few investigating the short-term outcome of preterm VLBW Italian children born in the second half of the 2000s. Neurodevelopmental assessment at 24 months revealed a marked reduction in major sequelae. Several risk factors for a poor neurodevelopmental outcome identified in children born in earlier periods were confirmed in these children born in recent years.

Central venous catheters in premature babies: radiological evaluation, malpositioning and complications.

Central venous catheters are important in the care for prematurely born children in the neonatal intensive care unit. The purpose of this pictorial essay is to illustrate correct positioning, malpositioning and possible complications of such devices.

BNP concentrations and cardiovascular adaptation in preterm and fullterm newborn infants.

To evaluate and compare cardiovascular adaptation of 36 preterm and 34 fullterm newborns, we analyzed BNP concentration and echocardiographic parameters at day 3 of life and at day 28 (+/-2). On day 3 BNP concentrations (pg/ml) resulted higher in PDA preterm group (n=11; 125, IQR 56.1-301) than preterm without PDA (n=25; 25.5 IQR 10.9-49; p<0.001) than fullterms (n=34; 55.1 IQR 23.6-82.7; p=0.013). No difference resulted in all groups at 28days (respectively: 12.7 IQR 4.9-23.8; 15.6 IQR 10-22; 8.9 IQR 5.6-20.6). Because of the newborns' growth, all echocardiographic parameters increased with linear relationship with body weight. On day 3 BNP concentration and echocardiographic parameters were not correlated besides LA/AO in preterms with PDA (p=0.0015). On day 28, BNP was significantly correlated with mVTI (p=0.019), M (p=0.007) and LA (p=0.005) in fullterms and only with LA (p=0.007) in preterms. In conclusion, BNP concentrations and echocardiographic measures confirm that preterm, and fullterm newborns conduct themselves in a similar manner during the transition from foetal to post-natal circulation, reaching low levels at a month of life. The presence of PDA during first days of life has no significant impact in this adaptation. LA is the echocardiographic parameter mostly related to BNP concentration in the newborns.

Persistent pulmonary hypertension of the newborn refractory to inhaled nitric oxide-treated with milrinone: a case report.

Current therapy of persistent pulmonary hypertension of the newborn (PPHN) consists of optimal ventilation, hemodynamic support and selective vasodilatation with inhaled nitric oxide (iNO). We present herein a case of PPHN non-responsive to iNO but treated successfully with a combination of iNO and intravenous milrinone, a phosphodiesterase III inhibitor. This case suggests that the drug may be a useful adjunctive treatment in the management of PPHN.

Two-year follow-up of the pharmacokinetics of immunosuppressive drugs in a neonate who underwent heart transplantation.

The pharmacokinetic properties of immunosuppressive drugs are quite different in newborns than in adults and few studies describe the pharmacokinetics of these drugs in pediatric heart transplant recipients. We report on the two-year follow up of a neonate who underwent heart transplantation for Hypoplastic Left Heart Syndrome on day of life 9. Two different immunosuppressive regimens were used: cyclosporine, azathioprine and prednisone in the early postoperative period, followed by the routine tacrolimus and mycophenolate mofetil combination plus prednisone from post-transplant day 22. Our findings demonstrate marked variability in immunosuppressive pharmacokinetic profiles early post-transplant. Frequent monitoring of drug levels is required to ensure that they remain within the therapeutic range. After the first 2-3 months post-transplant, changes in immunosuppressive drug levels are less marked and correlate more with the administered dosage.

Air embolism in the newborn: rare complication of intensive care therapy in children.

Systemic air embolism in neonates, either premature or full term, necessitating mechanical ventilation is a devastating and usually fatal condition. We describe three cases of this complication, two in mechanically assisted preterm babies, and one in a full-term dysmorphic patient. Causes and possible management are described.

Correlation between cord blood, perinatal BNP values and echocardiographic parameters in healthy Italian newborns.

We evaluated the correlation between brain natriuretic peptide (BNP) in umbilical cord blood after normal pregnancy, in blood samples of twenty-nine Italian healthy newborns and paired echocardiographic parameters. Plasma BNP was evaluated in UCB (T0) and in blood on day 3 (T1), 30 (T2) of life. Echocardiographic parameters were recorded at T1 and T2. Median of BNP concentrations in cord blood was 8.6 pg/ml. Median BNP concentrations on T1 was 59.2 pg/ml, on T2 was 8.7 pg/ml. Significantly higher BNP concentrations were reported on T1 than T0 and T2 (p<0.0001), while no significant difference resulted between T0 and T2. Plasma BNP at T2 was significantly correlated with mVTI (p=0.006), E wave (p=0.004), LA (p=0.047), LVPW (p=0.004), M (p=0.025). No correlation was found with SF% and E/A. Our results confirm that in healthy and term neonates the cord blood BNP concentrations are low. On T1 BNP values are high with wide ranges because of physiological adjustment to postnatal circulation. When echocardiographic parameters are in normal ranges, BNP concentrations return to low levels on day 30. In healthy newborns left ventricular filling, LA size and M seem to influence BNP levels rather than left ventricular systolic and diastolic function.

Candida albicans in a neonatal intensive care unit: antifungal susceptibility and genotypic analysis.

Invasive candidiasis in neonates has become an increasing problem over the past decade in Neonatal Intensive Care Units (NICUs). From August 2005 to January 2006, six invasive candidiasis occurred in neonates in NICU of the S. Matteo hospital of Pavia. The study focused on the species involved and their in vitro antifungal susceptibility. Genotyping was conducted to determine clonal relatedness. A total of 22 yeasts were isolated from different biological samples of neonates during six months. The infants were infected with or colonized by Candida albicans and six patients developed C. albicans deep infections. The genotyping of the transposable intron region of C. albicans strains showed that they belonged to the genotype A (17 isolates) and genotype B (5 isolates). The RAPD confirmed these results. These data suggest that nosocomial transmission of C. albicans could be take into account as a mode of acquisition by neonates in NICUs at this hospital.