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Term and preterm neonates have very few circulating Tfh-like cells (cTfh), and no circulating Tfr-like cells. Neonatal cTfh are CXCR5lo PD-1lo CD45RAhi , suggestive of a naive, possibly recently activated phenotype. CXCL13 is high at birth, but decreases rapidly in the first weeks of life. Overall, signs of GC activity in human neonates are weak, even in those born prematurely or after sepsis. Term and preterm neonates have very few circulating Tfh-like cells (cTfh), and no circulating Tfr-like cells. Neonatal cTfh are CXCR5(lo)PD-1(lo)CD45RA(hi), suggestive of a naive, possibly recently activated phenotype. CXCL13 is high at birth, but decreases rapidly in the first weeks of life. Overall, signs of GC activity in human neonates are weak, even in those born prematurely or after sepsis. (dagger)

In the context of SARS-CoV-2 pandemic, the hospital management of mother-infant pairs poses to obstetricians and neonatologists previously unmet challenges. In Lombardy, Northern Italy, 59 maternity wards networked to organise the medical assistance of mothers and neonates with suspected or confirmed SARS-CoV-2 infection. Six “COVID-19 maternity centres” were identified, the architecture and activity of obstetric and neonatal wards of each centre was reorganised, and common assistance protocols for the management of suspected and proven cases were formulated. Here, we present the key features of this reorganization effort, and our current management of the mother-infant dyad before and after birth, including our approach to rooming-in practice, breastfeeding and neonatal follow-up, based on the currently available scientific evidence. Considered the rapid diffusion of COVID-19 all over the world, we believe that preparedness is fundamental to assist mother-infant dyads, minimising the risk of propagation of the infection through maternity and neonatal wards.

Background and objectives Despite low incidence of early-onset sepsis, the majority of preterm newborns receive early antibiotic prophylaxis. Our aim was to assess reference ranges of Presepsin during the first 48 h of life in preterm infants and to evaluate the possible influence of neonatal and maternal factors on its values. Methods This observational study consecutively enrolled newborns ≤ 32 weeks of GA at 0–6 h of life. Enrolled infants were sampled for blood culture, complete white blood cell (WBC) count, and P-SEP at 0–6 (T0) h of life and for P-SEP at 12 ± 3 (T1), 24 ± 3 (T2), and 48 ± 6 (T3) h of life. Cases of EOS were not considered for the statistical analysis. Results Data analysis was performed for 183 patients. P-SEP median values were 583 ng/L at T0 (IQR 405–800 ng/L, 5th and 95th percentiles 204 and 1200 ng/L), 614 ng/L at T1 (IQR 450–812 ng/L, 5th and 95th percentiles 262 and 1171 ng/L), 604 ng/L at T2 (IQR 445–825 ng/L, 5th and 95th percentiles 292 and 1302 ng/L) and 513 ng/L at T3 (IQR 371–734 ng/L, 5th and 95th percentiles 249 and 1278 ng/L). P-SEP values are negatively associated to gestational age (GA) at T0, T1, and T2. Conclusions We determined for the first time the reference ranges of P-SEP during the first 48 h of life in very preterm infants and provided its percentile distribution at T0, T1, T2 and T3. P-SEP measurement was affected by GA at T0, T1, T2.

Objective To determine the frequency of abnormal findings on evaluation of neonates with congenital CMV infection who have a normal physical examination Study design Retrospective, 2-center study (1996–2017) that reviewed results of complete blood cell count and platelets, serum alanine aminotransferase (ALT) and bilirubin concentrations, eye examination, cranial ultrasonography or other neuroimaging, and brainstem evoked responses performed on neonates with congenital CMV infection and a normal physical examination Results Of 34 infants with congenital CMV infection and a normal physical examination, 56% (19/34) had ≥1 abnormality: 39%, elevated ALT concentration; 45%, abnormal neuroimaging (five, lenticulostriate vasculopathy; six, intraventricular hemorrhage; four, calcifications); 12%, anemia; 16%, thrombocytopenia; and 3%, chorioretinitis. Seven (21%) infants had sensorineural hearing loss, and 18 infants received antiviral therapy. Conclusion Some infants with congenital CMV infection and a normal physical examination had abnormalities on laboratory or neuroimaging evaluation, which in some cases prompted antiviral treatment.

Esophageal lung is a rare bronchopulmonary foregut malformation characterized by an anomalous origin of one of the main bronchi which arises from the esophagus. Less than 30 cases are reported in the literature. Therefore, there are no standardized guidelines for the treatment of this condition. We report a case of right esophageal lung diagnosed in a neonate. The patient was treated with thoracoscopic closure of the ectopic main bronchus in the neonatal period, followed by delayed pneumonectomy at 5 months of age. No prosthetic substitute was implanted in the ipsilateral hemithorax after pneumonectomy. The patient is now 4 years old and doing well, postpneumonectomy syndrome was never observed. Our strategy and the possible alternatives are discussed here.

Introduction A potential complication of term prelabor rupture of membranes (term PROM) is chorioamnionitis with an increased burden on neonatal outcomes of chronic lung disease and cerebral palsy. The purpose of the study was to analyze the efficacy of a standing clinical protocol designed to identify women with term PROM at low risk for chorioamnionitis, who may benefit from expectant management, and those at a higher risk for chorioamnionitis, who may benefit from early induction. Material and methods This retrospective study enrolled all consecutive singleton pregnant women with term PROM. Subjects included women with at least one of the following factors: white blood cell count ≥ 15×100/μL, C-reactive protein ≥ 1.5 mg/dL, or positive vaginal swab for beta-hemolytic streptococcus. These women comprised the high risk (HR) group and underwent immediate induction of labor by the administration of intravaginal dinoprostone. Women with none of the above factors and those with a low risk for chorioamnionitis waited for up to 24 hours for spontaneous onset of labor and comprised the low-risk (LR) group. Results Of the 884 consecutive patients recruited, 65 fulfilled the criteria for HR chorioamnionitis and underwent immediate induction, while 819 were admitted for expectant management. Chorioamnionitis and Cesarean section rates were not significantly different between the HR and LR groups. However, the prevalence of maternal fever (7.7% vs. 2.9%; p = 0.04) and meconium-stained amniotic fluid was significantly higher in the HR group than in LR group (6.1% vs. 2.2%; p = 0.04). This study found an overall incidence of 4.2% for chorioamnionitis, 10.9% for Cesarean section, 0.5% for umbilical artery blood pH < 7.10, and 1.9% for admission to the neonatal intensive care unit. Furthermore, no confirmed cases of neonatal sepsis were encountered. Conclusions A clinical protocol designed to manage, by immediate induction, only those women with term PROM who presented with High Risk factors for infection/inflammation achieved similar maternal and perinatal outcomes between such women and women without any risks who received expectant management. This reduced the need for universal induction of term PROM patients, thereby reducing the incidence of maternal and fetal complications without increasing the rate of Cesarean sections.

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pathophysiology of the placenta and its impact on pregnancy outcome has not yet been fully elucidated. Here, we present a comprehensive clinical, morphological, and molecular analysis of placental tissues from pregnant women with and without SARS-CoV-2 infection. SARS-CoV-2 could be detected in half of placental tissues from SARS-CoV-2-positive women. The presence of the virus was not associated with any distinctive pathological, maternal, or neonatal outcome features. SARS-CoV-2 tissue load was low in all but one patient who exhibited severe placental damage leading to neonatal neurological manifestations. The placental transcriptional response induced by high viral load of SARS-CoV-2 showed an immunopathology phenotype similar to autopsy lung tissues from patients with severe coronavirus disease 2019. This finding contrasted with the lack of inflammatory response in placental tissues from SARS-CoV-2-positive women with low viral tissue load and from SARS-CoV-2-negative women. Importantly, no evidence of vertical transmission of SARS-CoV-2 was found in any newborns, suggesting that the placenta may be an effective maternal-neonatal barrier against the virus even in the presence of severe infection. Our observations suggest that severe placental damage induced by the virus may be detrimental for the neonate independently of vertical transmission.

BackgroundThe impact of the Covid-19 infection on patients with chronic endocrine disease is not fully known. We describe here the first case of a pregnant woman with Covid-19 acute infection and non-classical congenital adrenal hyperplasia (NCAH).Case descriptionA woman at 36 weeks of gestation was referred to our Maternity Hospital for premature rupture of membranes (PROM). Her medical history was positive for NCAH on chronic steroid replacement till the age of 17 years (cortisone acetate and dexamethasone, both in the morning). At admission, her naso-oro-pharyngeal swab resulted positive for SARS-CoV-2. Due to hyperpyrexia and late preterm PROM, cesarean section was planned, and she was started on a 100 mg-bolus of hydrocortisone, followed by continuous infusion of 200 mg/24 h. A female neonate in good clinical condition and with a negative nasopharyngeal Covid-19 swab was delivered. On secondpostpartumday, the mother was in good condition and was switched to oral steroid therapy. On thirdpostpartumday she worsened, with radiological signs of acute pulmonary embolism. Oro-tracheal intubation and mechanical ventilation were started, and she was switched back to intravenous steroid therapy. On April 30, pulmonary embolism was resolved, and on May 13th she was discharged in good condition.ConclusionsWe report the first case of Covid-19 acute infection that occurred in late-pregnancy in a woman with NCAH on chronic steroid replacement. The management of the patient in a reference center with early involvement of a multidisciplinary team granted prompt care and adequate protection for all the involved sanitary operators.

Importance The management of mother-infant dyads during the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic constitutes a major issue for neonatologists. In mothers with SARS-CoV-2 infection, current recommendations suggest either to separate the dyad or encourage protected rooming-in under appropriate precautions. No data are available regarding the risk of mother-to-infant transmission of SARS-CoV-2 during rooming-in. Objective To evaluate the risk of postnatal transmission of SARS-CoV-2 from infected mothers to their neonates following rooming-in and breastfeeding. Design, Setting, and Participants A prospective, multicenter study enrolling mother-infant dyads from March 19 to May 2, 2020, followed up for 20 days of life (range, 18-22 days), was performed. The study was conducted at 6 coronavirus disease 2019 maternity centers in Lombardy, Northern Italy. Participants included 62 neonates born to 61 mothers with SARS-CoV-2 infection who were eligible for rooming-in practice based on the clinical condition of the mother and infants whose results of nasopharyngeal swabs were negative at birth. Exposures Mothers with SARS-CoV-2 infection were encouraged to practice rooming-in and breastfeeding under a standardized protocol to minimize the risk of viral transmission. Main Outcomes and Measures Clinical characteristics and real-time reverse transcriptase-polymerase chain reaction for SARS-CoV-2 on neonatal nasopharyngeal swabs at 0, 7, and 20 days of life. Results Of the 62 neonates enrolled (25 boys), born to 61 mothers (median age, 32 years; interquartile range, 28-36 years), only 1 infant (1.6%; 95% CI, 0%-8.7%) was diagnosed as having SARS-CoV-2 infection at postbirth checks. In that case, rooming-in was interrupted on day 5 of life because of severe worsening of the mother’s clinical condition. The neonate became positive for the virus on day 7 of life and developed transient mild dyspnea. Ninety-five percent of the neonates enrolled were breastfed. Conclusions and Relevance The findings of this cohort study provide evidence-based information on the management of mother-infant dyads in case of SARS-CoV-2 maternal infection suggesting that rooming-in and breastfeeding can be practiced in women who are able to care for their infants.

Human herpesvirus 6 (HHV-6) can integrate its genome in human chromosomes and be germline transmitted (inherited chromosomally integrated HHV-6). We report a case of chromosomally integrated HHV-6 inherited from the mother unexpectedly diagnosed in a septic neonate. Since HHV-6 has recently been included in multiplex polymerase chain reaction assays for meningitis/encephalitis, diagnosing inherited chromosomally integrated HHV-6 status is essential to avoid misdiagnosis of active HHV-6 infection and unnecessary antiviral treatment.

SARS‐CoV‐2 infection in the neonatal period poses previously unmet challenges to obstetricians and neonatologists, but several key questions are yet to be answered. Few cases of presumed in utero vertical transmission of the virus from infected mothers to fetuses have been reported, but stronger evidence is needed, from larger datasets with multiple biospecimens rigorously analyzed. Whether acquired before or after birth, SARS‐CoV‐2 infection in neonates can be symptomatic, but our comprehension of neonatal immune response and the subsequent clinical characteristics of COVID‐19 in early life are incomplete. Finally, the pandemic challenged several dogmas regarding the management of mother‐infant dyads, and again more robust data are needed to support the formulation of evidence‐based guidelines. Here, we briefly summarize existing evidence and key unresolved questions about SARS‐CoV‐2 infection and COVID‐19 in the neonatal period.

Weaning from parenteral to enteral nutrition is a critical period to maintain an adequate growth in very low birth weight preterm infants (VLBWI). We evaluated the actual daily nutritional intakes during the transition phase (TP) in VLBWI with adequate and inadequate weight growth velocity (GV &ge, 15 vs. GV &lt, 15 g/kg/day). Fat-free mass (FFM) at term-corrected age (TCA) was compared between groups. Based on actual nutritional intakes of infants with adequate growth, we defined a standardized parenteral nutrition bag (SPB) for the TP. One hundred and six VLBWI were categorized as group 1 (G1): [GV &lt, 15 (n = 56)] and group 2 (G2): [GV &ge, 15 (n = 50)]. The TP was divided into two periods: main parenteral nutritional intakes period (parenteral nutritional intakes &gt, 50%) (M-PNI) and main enteral nutritional intakes period (enteral nutritional intakes &gt, 50%) (M-ENI). Anthropometric measurements were assessed at discharge and TCA, FFM deposition at TCA. During M-PNI, G2 showed higher enteral protein intake compared to G1 (p = 0.05). During M-ENI, G2 showed higher parenteral protein (p = 0.01) and energy intakes (p &lt, 0.001). A gradual reduction in SPB volume, together with progressive increase in enteral volume, allowed nutritional intakes similar to those of G2. At TCA, G2 had higher FFM compared to G1 (p = 0.04). The reasoned use of SPB could guarantee an adequate protein administration, allowing an adequate growth and higher FFM deposition.

Hexavalent vaccines, protecting against six diseases (diphtheria, tetanus, pertussis [DTaP], poliovirus, hepatitis B virus [HBV], and Haemophilus influenzae type b [Hib], are routinely the standard of care in Europe. The use of combined vaccines allows the reduction of number of injections and side effects, the reduction of costs, and the increase in adherence of the family to the vaccination schedule both in terms of the number of doses and timing. The safety profile, efficacy and effectiveness of hexavalent vaccines have been extensively documented in infants and children born at term, and data are accumulating in preterm infants. Hexavalent vaccines are particularly important for preterm infants, who are at increased risk for severe forms of vaccine preventable diseases. However, immunization delay has been commonly reported in this age group. All the three hexavalent vaccines currently marketed in Italy can be used in preterm infants, and recent data confirm that hexavalent vaccines have a similar or lower incidence of adverse events in preterm compared to full-term infants; this is likely due to a weaker immune system response and reduced ability to induce an inflammatory response in preterm infants. Apnoea episodes are the adverse events that can occur in the most severe preterm infants and / or with history of respiratory distress. The risk of apnoea after vaccination seems to be related to a lower gestational age and a lower birth weight, supporting the hypothesis that it represents an unspecific response of the preterm infant to different procedures. High seroprotection rates have been reported in preterm infants vaccinated with hexavalent vaccine. However, a lower gestational age seems to be associated with lower antibody titres against some vaccine antigens (e.g. HBV, Hib, poliovirus serotype 1, and pertussis), regardless of the type of hexavalent vaccine used. Waiting for large effectiveness studies, hexavalent vaccines should be administered in preterm infants according to the same schedule recommended for infants born at term, considering their chronological age and providing an adequate monitoring for cardio-respiratory events in the 48–72 h after vaccination, especially for infants at risk of recurrence of apnoea.

Background Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain. Aim To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk. Study Design This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM. Results (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18–0.64; p Conclusion Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS.

Systemic inflammation in neonates is attributable to an infection in almost all cases. When inflammation persists, an autoinflammatory disease should be promptly suspected. We report here a case of mevalonate kinase deficiency (MKD) that presented at birth with mild symptoms and signs suggestive for a perinatal infection, together with the uncommon finding of interstitial lung disease. An extensive diagnostic work-up, performed after ineffective antibiotic treatment, demonstrated high levels of mevalonic acid in urine (7024 mM/M of creatinine, normal value0.1). Next-generation sequencing showed a rare c.709A T (p.T237S) homozygous mutation in the MVK gene, consistent with MKD. Treatment with anakinra led to a prompt resolution of symptoms and a sharp drop in serum inflammatory markers. The patient is now six months-old, currently undergoing evaluation for hematopoietic stem-cell transplantation. To our knowledge, this is the first case of MKD presenting within the first week of life with interstitial lung disease.

BackgroundThe early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged Methods and findingsNeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052).ConclusionsWithin this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.

Rationale: Lymphatic malformations (LMs) are rare and benign anomalies resulting from the defective embryological development of the primordial lymphatic structures. Due to their permeative growth throughout all tissue layers, treatment is often challenging. Small asymptomatic lesions can be conservatively managed, while symptomatic lesions require active management. Surgery has been historically considered the treatment of choice, but today less invasive therapeutic options are preferred (sclerotherapy, laser therapy, oral medications). However, there are not uniform therapeutic protocols. Sirolimus is an oral medication that has been reported to be effective in the recent literature. Here we present the case of 4 newborns with giant multicystic lymphangioma treated with oral sirolimus after surgical resection had failed. Patient concerns: At birth the LMs were clinically appreciated as giant masses involving different organs and structures. Diagnoses: All patients had a prenatal diagnosis of giant multicystic lymphangioma confirmed at histological and cytological analysis. Interventions: Patients were treated with oral sirolimus after unsuccessful surgical resection. Outcomes: In all patients, sirolimus determined an overall reduction of the mass and a global involution from the macro- to the microcystic composition. Sirolimus was safe and poor disadvantages had been observed. The main and isolated adverse effect at laboratory analysis was progressive dyslipidemia, with increasing levels of total cholesterol and triglycerides. Lessons: To date, our experience with sirolimus in the management of LMs is favorable. We recommend the use of sirolimus after unsuccessful surgical excision have been tried or when the surgical approach is not feasible. A multidisciplinary follow-up is needed to monitor disease evolution.

Objective To determine the frequency of detection of cytomegalovirus (CMV) among infants evaluated for late-onset sepsis in the neonatal intensive care unit (NICU). Methods This study was a prospective cohort study. Results During the 13-month study, 84 infants underwent 116 sepsis evaluations, and CMV DNA was detected in saliva in three (4%) infants (median: gestational age 28 weeks, birth weight 950 g), representing 5% (n=6) of all sepsis evaluations. One infant had CMV DNA detected in saliva in all four sepsis evaluations. Two infants had acquired CMV infection, while the timing of CMV acquisition could not be determined in one infant. Two of the three infants had concomitant Gram-negative bacteremia and urinary tract infections (UTIs), two developed severe bronchopulmonary dysplasia (BPD) and none died. Conclusion Detection of CMV DNA in saliva occurred in 4% of infants and 5% of sepsis evaluations. Persistence of CMV DNA shedding in saliva made attribution of clinical illness difficult to ascertain.

Objective: To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. Study design: This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. Results: Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. Conclusion: Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. Trial registration: isrctn.org: ISRCTN53107700.

Immunization is key to preventing infectious diseases, a leading cause of death early in life. However, due to age-specific immunity, vaccines often demonstrate reduced efficacy in newborns and young infants as compared to adults. Here, we combined in vitro and in vivo approaches to identify adjuvant candidates for early life immunization. We employed newborn and adult bone marrow-derived dendritic cells (BMDCs) to perform a screening of pattern recognition receptor agonists and found that the stimulator of interferon genes ligand 2′3′-cGAMP (hereafter cGAMP) induces a comparable expression of surface maturation markers in newborn and adult BMDCs. Then, we utilized the trivalent recombinant hemagglutinin (rHA) influenza vaccine, Flublok, as a model antigen to investigate the role of cGAMP in adult and early life immunization. cGAMP adjuvantation alone could increase rHA-specific antibody titers in adult but not newborn mice. Remarkably, as compared to alum or cGAMP alone, immunization with cGAMP formulated with alum (Alhydrogel) enhanced newborn rHA-specific IgG2a/c titers ~400-fold, an antibody subclass associated with the development of IFNγ-driven type 1 immunity in vivo and endowed with higher effector functions, by 42 days of life. Highlighting the amenability for successful vaccine formulation and delivery, we next confirmed that cGAMP adsorbs onto alum in vitro. Accordingly, immunization early in life with (cGAMP+alum) promoted IFNγ production by CD4+ T cells and increased the proportions and absolute numbers of CD4+ CXCR5+ PD-1+ T follicular helper and germinal center (GC) GL-7+ CD138+ B cells, suggesting an enhancement of the GC reaction. Adjuvantation effects were apparently specific for IgG2a/c isotype switching without effect on antibody affinity maturation, as there was no effect on rHA-specific IgG avidity. Overall, our studies suggest that cGAMP when formulated with alum may represent an effective adjuvantation system to foster humoral and cellular aspects of type 1 immunity for early life immunization.

Background Serratia marcescens (Sm) is a known cause of infection and colonization in neonates receiving intensive care. The aim of this study was to identify the risk factors for colonization and infection with Sm in Neonatal Intensive Care Unit (NICU) of a tertiary care Hospital. Methods A casecontrol study was conducted from January to December 2011 in neonates admitted to the NICU. Cases are patients with a microbiologically confirmed infection or colonization, controls were randomly chosen among patients admitted to the same NICU. Results Globally, 39 acquired infections or colonizations were identified. Among factors related to pregnancy, only premature delivery was independently associated to the risk of infection; as well as mechanical ventilation and catheterization for parenteral nutrition, considering indwelling devices. Prolonged administration with antibiotics were also related to the risk of infection. Among Sm strains which have been tested to antibiotics, all have been resistant to amoxicillin/clavulanic acid and to colistin. Conclusion This study confirms the association between Sm infection or colonization and low gestational age. Invasive medical devices and medications, strictly necessary in caresupport of preterm neonates, are likely related to Sm infection too. Preventive control strategies are expected to be effective in the control of Sm spread in NICUs.

Objective To determine the frequency of respiratory viral infections among infants who were evaluated for late-onset sepsis in the neonatal intensive care units (NICUs) of Parkland Memorial Hospital, Dallas, Texas; and Women & Infants Hospital, Providence, Rhode Island. Study design Prospective cohort study conducted from January 15, 2012 to January 31, 2013. Infants in the NICU were enrolled if they were inborn, had never been discharged home, and were evaluated for sepsis (at >72 hours of age) and antibiotic therapy was initiated. Infants had a nasopharyngeal specimen collected for detection of respiratory viruses by multiplex polymerase chain reaction within 72 hours of the initiation of antibiotic therapy. Their medical records were reviewed for demographic, clinical, radiographic, and laboratory data until NICU discharge. Results During the 13-month study, 8 of 100 infants, or 8 (6%) of the 135 sepsis evaluations, had a respiratory virus detected by polymerase chain reaction (2, enterovirus/rhinovirus; 2, rhinovirus; 2, coronaviruses; and 2, parainfluenza-3 virus). By bivariate analysis, the infants with viral detection were older (41 vs 11 days; P = .007), exposed to individuals with respiratory tract viral symptoms (37% vs 2%; P = .003), tested for respiratory viruses by provider (75% vs 11%; P

FilmArray Respiratory Panel (RP) (Idaho Technology, Inc., Salt Lake City, UT, USA) performance was retrospectively evaluated in respiratory samples collected from neonates in 2 reference neonatology units. Using the FilmArray RP assay, 121/152 (79.6%) samples were positive for at least 1 respiratory virus, while 31/152 (20.4%) were negative. FilmArray RP results were concordant in 68/72 (94.4%) respiratory samples tested with laboratory-developed real-time PCR assays, while in 4/72 (5.6%) samples, the FilmArray RP assay detected an additional virus (2 human rhinovirus/enterovirus and 2 bocavirus). In addition, FilmArray RP results for 70 of 80 (87.5%) respiratory samples tested were concordant with the Seegene Seeplex RV15® detection assay (Seegene, Inc., Seoul, South Korea), while 10/80 (12.5%) were discordant. The advantages of the FilmArray RP are the rapid detection of respiratory viruses (1 hour), the wide number of pathogens detectable in a single assay, and the reduced hands-on time.

Hairy polyps are rare developmental lesions, which present as masses mainly consisting of fatty tissue covered by skin, seldom localized in the nasopharynx, causing respiratory obstruction. We describe the case of a female newborn affected by a hairy polyp arising from the left Eustachian tube, who presented severe respiratory distress soon after birth. The polyp was successfully removed transorally under videoendoscopic guidance. This case highlights the importance of including hairy polyp in the differential diagnosis of respiratory distress at birth because this type of tumor can be lethal and requires prompt treatment. A transoral endoscopy-guided approach can allow successful and minimally invasive excision even in a newborn.

Rotavirus (RV) is the leading cause of severe acute gastroenteritis (GE) in infants worldwide. Several vaccines against RV were developed to reduce disease burden, hospitalization rates and health utilization costs. RV GE is a serious disease in preterm (PT) infants, and the administration of RV vaccine to these at-risk subjects at the proper time could have great clinical relevance. However, most data on the efficacy and safety of RV vaccinations were collected in healthy full-term infants, and few studies investigated PT infants. The lack of studies in PT infants may explain why neonatologists in several neonatal intensive care units (NICUs) do not follow the official recommendations, which indicate that RV vaccine may be administered in hospitals. Increasing neonatologists' knowledge on the efficacy and safety of RV vaccines and defining PT candidates for vaccination and the necessary precautions are extremely important to avoid potential vaccine virus transmission and improve RV vaccination coverage in PT infants. Further studies should analyse the impact of vaccination of PT infants of different gestational ages and various clinical histories in stable conditions in the NICU with a careful monitoring of adverse events to the vaccine and RV GE occurrence. Only data that confirm the efficacy and safety of RV vaccines in large numbers of PT infants with different characteristics will convince neonatologists to use RV vaccines in PT infants hospitalized in NICUs.

Septic shock, occurring in about 1% of neonates hospitalized in neonatal intensive care unit (NICU), is a major cause of death in the neonatal period. In the 1980s and 90s, exchange transfusion (ET) was reported by some authors to be effective in the treatment of neonatal sepsis and septic shock. The main aim of this retrospective study was to compare the mortality rate of neonates with septic shock treated only with standard care therapy (ScT group) with the mortality rate of those treated with ScT and ET (ET group). All neonates with septic shock admitted to our NICU from 2005 to 2015 were included in the study. Overall, 101/9030 (1.1%) neonates had septic shock. Fifty neonates out of 101 (49.5%) received one or more ETs. The mortality rate was 36% in the ET group and 51% in the ScT group (p = 0.16). At multivariate logistic regression analysis, controlling for potentially confounding factors significantly associated with death (gestational age, serum lactate, inotropic drugs, oligoanuria), ET showed a marked protective effect (Odds Ratio 0.21, 95% Confidence Interval: 0.06–0.71; p = 0.01). The lack of observed adverse events should encourage the use of this procedure in the treatment of neonates with septic shock.

Fungal colonisation by Candida spp. affects a high proportion of VLBW neonates in NICU. However, few data are available on the clinical characteristics of colonisation in preterm infants who are colonised at baseline via vertical transmission, compared to preterms who become colonised during their stay in NICU via horizontal transmission.We reviewed the database of a multicentre, randomised trial of prophylactic fluconazole in VLBW neonates conducted in 8 Italian NICUs in the years 2004 and 2005 (Manzoni et al., NEJM 2007;356(24):2483-95). Per the protocol, all enrolled infants underwent weekly surveillance cultures from birth till discharge. We investigated the frequency of the two different modalities of Candida colonisation in this population, as well as the clinical and outcome characteristics possibly related to them.Overall, Candida colonisation affected 54 of 336 infants (16.1%). Baseline (i.e., detected3(rd) day of life) colonisation affected 16 (4.7%), and acquired 38 (11.4%), of the 54 colonised preterms. Infants with baseline colonisation had significantly higher birth weight (1229 ± 28 g vs. 1047 g ± 29, p = 0.01) and gestational age (30.2 wks ± 2.7 vs. 28.5 wks ± 2.6, p = 0.01), and were significantly more likely to limit progression from colonisation to invasive Candida infection when fluconazole prophylaxis was instituted (21.6% vs. 42.7%, p = 0.009). Isolation of C. parapsilosis was significantly more frequent in infants with acquired colonisation.Infants with baseline and acquired colonisation differ for demographics characteristics and for their response to fluconazole prophylaxis. This information may be useful for targeting more accurate management strategies for these two different groups of colonised preterms in NICU.

OBJECTIVE: This study was designed to evaluate the immunogenicity, safety, and tolerability of a monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in children aged 6 to 23 months who had different gestational ages (GAs) at birth. METHODS: The study involved 105 children: 35 preterm subjects with a GA of RESULTS: Of the 101 children who completed the study 32 out of 34 preterm subjects with a GA of CONCLUSIONS: A single dose of 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine evoked a significant immune response against pandemic influenza A/H1N1 virus in children aged 6 to 23 months even if their GA was

We report 2 neonates with human parechoviruses type 3 encephalitis. Both newborns presented with fever, irritability and seizures. Cerebrospinal fluid analyses were normal, but magnetic resonance imaging revealed white matter damage, suggesting human parechoviruse infection. Human parechoviruses type 3-RNA was detected in cerebrospinal fluid samples and in blood, stool, urine and respiratory samples, indicating the dissemination of the virus.

The data from the present investigation differ from those of the previous study. The new version of hydrolysed protein formula did not induce changes in insulinaemia or in the insulinaemia/glycaemia ratio in pre- and postprandial samples when compared with the intact protein formula. The investigation also confirmed that branch chain aminoacids regulate insulin secretion and that the length of chain is insulinotropic for fatty acids, while the degree of unsaturation is not able to reduce insulin secretion in the newborn baby. This could be caused by stimulation of insulin output activated by the C20:5 n 3; the effects of fatty acids are probably related more to the variable composition of cell membrane than to the fatty acids circulating levels.

Aim: Since 1997 a newborn hearing screening programme has been implemented by the U.O. Neurologia-Neurofisiopatologia and Dipartimento di Neonatologia of the Istituti Clinici di Perfezionamento ICP in Milan for both babies with no risk and those at risk of hearing impairment. This programme was named the Milan Project. Methods: The protocol for no-risk babies consisted of three stages: in the first two stages, newborns were tested with transient click-evoked otoacoustic emissions (TEOAE), in the third one with conventional auditory brainstem responses (ABR). The first TEOAE test was performed by 36 h of age, before discharge, the second one after 15–30 d in case of referral, and the third one, by ABR, for those babies who failed the second TEOAE stage. Newborns at audiological risk were submitted to conventional ABR before the third month of corrected age. Some of this latter population was also submitted to the TEOAE test. The entire tested population (no-risk babies and newborns at audiological risk) consisted of 19 777 babies: 19 290 without risk (“no risk”) and 487 at risk (“at risk”). Results: During the course of the Milan Project, hearing impairment (ABR threshold equal to or greater than 40 dB nHL) was identified in 63 newborns (19 from the no-risk and 44 from the at-risk population), with a prevalence of 0.32%. Bilateral hearing impairment (BHI) was found in 33 newborns (10 from the no-risk and 23 from the at-risk population), corresponding to 0.17%. Among infants with bilateral hearing impairment, 30.3% had no risk factors. The prevalence of hearing impairment was determined on days 15–30 after birth. Conclusions: The results show that the implementation of a hospital-based, universal neonatal hearing screening programme for babies with and without audiological risk is feasible and effective. The effectiveness of the programme has increased as a function of the years since its inception, with a strong decrease in the referral rate. Further improvement is obtained if the TEOAE measurements are repeated in cases of referral scoring before discharge.

Objective Presepsin (soluble CD14 subtype) has been shown to be beneficial as a sepsis marker in adults. Nevertheless, very few data are available in neonates. The aim of the present study was to determine reference ranges of presepsin in term and preterm neonates. Methods Healthy term neonates and preterm neonates without clinical signs of infection admitted to the Neonatal Unit were consecutively enrolled. Presepsin concentrations in whole blood were measured using a point-of-care assay system located in the Unit. Demographic data, antenatal and perinatal variables commonly affecting C-reactive protein and procalcitonin values were considered. Results Of the 684 neonates enrolled in the study, 484 (70.8%) were born at term and 200 (29.2%) were preterm (24–36 weeks’ gestation). In term infants, presepsin median value was 603.5 pg/mL (interquartile range: 466.5–791 pg/mL; 5th and 95th centiles: 315 and 1178 pg/mL respectively). In preterm infants, presepsin median value was slightly higher, equal to 620 pg/mL (interquartile range: 503–864 pg/mL; 5th and 95th centiles: 352 and 1370 pg/mL respectively). The reference ranges of presepsin we determined were much higher than those seen in healthy adults. No correlation between presepsin levels and postnatal age was observed, as well as no significant difference was demonstrated in preterm neonates at different gestational ages. None of the variables analyzed affected presepsin levels at a clinical significant extent. Conclusion For the first time, this study provides reference ranges of presepsin in term and preterm neonates. Having reliable reference values is crucial for obtaining an adequate diagnostic accuracy. Based on our results, most variables commonly affecting C-reactive protein and procalcitonin values do not affect presepsin levels, which suggests that presepsin could be an effective sepsis marker. Further investigations in large groups of neonates with sepsis are needed to determine the diagnostic and prognostic value of this biomarker.

The term chorioamnionitis is used to refer to an intrauterine infection/inflammation occurring between the maternal tissues and the fetal membranes (choriodecidual space) or in the fetal annexes (chorioamniotic membranes, amniotic fluid, umbilical cord). Histological examination of the placenta is the gold standard for diagnosis. However, clinical, biochemical and microbiological criteria are also used to define the disease. The literature contains a large body of evidence showing that chorioamnionitis is the leading cause of very preterm birth and, therefore, contributes significantly to neonatal morbidity and mortality. In recent decades, numerous studies have attempted to establish whether, and to what extent, intrauterine infection/inflammation might negatively affect the short- and long-term outcome of preterm infants. The question is still unanswered. The discrepancy observed across studies can be attributed largely to the use of different inclusion and exclusion criteria, diagnostic criteria and methods, and to whether or not potential confounding factors, such as gestational age were considered. Anyhow, the association between chorioamnionitis and severe prematurity requires serious efforts by researchers to clarify the mechanisms linking intrauterine infection/inflammation with preterm birth, and thus to identify strategies that may guide clinicians' diagnostic and therapeutic choices, with regard to both mothers and infants.

Cytomegalovirus (CMV) infection is the most frequent congenital infection in humans. Its prevalence and the frequency of disabling sequelae must be assessed in different populations to permit the formulation or assessment of preventive measures.To check the prevalence of congenital infection and seroprevalence in Italy; to verify the rate of sensorineural hearing loss (SNHL) in infected infants; and to assess the proportion of children with SNHL attributable to congenital CMV infection.Diagnosis of congenital CMV infection was sought in 9032 children born between March 2002 and February 2003 by testing for viral DNA [CMV dried blood spot (DBS) test] in each newborn's Guthrie card and confirmation by isolation of CMV from urine collected in the first 3 weeks of life; CMV IgG testing in 1200 women of childbearing age; clinical and audiologic tests in the first 24 months for infected children; CMV DBS tests on the Guthrie cards collected from screening centers for 77 children (3 months-5 years) presenting SNHL of 40 dB or more.CMV infection was diagnosed in 14 asymptomatic and 2 symptomatic newborns (0.18%). CMV seroprevalence was 80%. In 2 infected infants, transient, unilateral SNHL was found. Nineteen of the 71 children with SNHL70 dB were congenitally infected.The prevalence of congenital CMV infection is low in Italy. Population characteristics limiting the circulation of CMV strains in adult women might explain this. The fact that CMV contributes to significant SNHL highlights the need for preventive measures.

Background. Serratia marcescens, a Gram-negative organism, is a well-recognized nosocomial pathogen, especially in Neonatal Intensive Care Units (NICUs). Even if multiple point sources have been identified, the source of an outbreak often remains unknown. Because an outbreak of S. marcescens can spread rapidly, closing the Unit sometimes is necessary. Here, we report on an outbreak of S. marcescens occurred in our NICU and describe the control measures taken to stop the epidemic without closing the Unit. Material and Methods. Our Unit is a 56-bed Unit composed of two areas: a 23-bed (4 rooms) intensive-care and a 33-bed (6 rooms) intermediate-care area. After some cases of S. marcescens infection were identified during a 3-month period, a prospective epidemiological study was performed in both areas during a period of 8 months. Surveillance cultures were obtained from all neonates (pharynx, rectum, eyes, ears) at admission, at room-changing and twice weekly, from medical and nursing staff (pharynx, rectum) and from the environment (sinks, ventilators, incubators, soap dispensers, disinfectants, breast pumps, work surfaces). The following control measures were also taken: universal precautions were intensified (handwashing, gloves, masks), education of the staff was stressed, a survey was instituted to check the observance of the control measures, admissions to the NICU were limited and infected/colonized babies were strictly cohorted. Because the outbreak continued despite these control measures, we separated new admissions from hospitalized babies by using two ways in the Unit: a clean way (green) and a dirty way (red) with nurses, rooms and everything different between the green and the red babies. Results. During the study period, 589 neonates underwent surveillance cultures (14.156 samples); 32/589 (5%) infants had positive swabs. Four (12.5%) of the 32 colonized infants had clinical signs of infection: sepsis-like symptoms (2 cases) and conjunctivitis (2 cases). Twenty-two (68.8%) of the 32 colonized infants became positive in the intensive-care area; the median time from admission to the first positive culture was 13 days (range 6-83). Risk factors for infection/colonization were low birthweight (green way and the red way.Conclusions. In this outbreak, no evidence of environmental or staff reservoirs was shown. Transmission was likely horizontal, from newborn to newborn, through the hands of medical and nursing staff and the infected/colonized infants were themselves the reservoir of the pathogen. Probably, the organism was introduced into our NICU from an ex-preterm patient from another hospital (index case). The use of a clean way and a dirty way, in addition to the other control measures, appeared the most effective practice to stop the epidemic without closing the Unit.

No international guidelines are available for the treatment of oral tongue cancer during pregnancy. Six patients with tongue cancer during pregnancy were identified by a retrospective chart review. In three of the cases we did not follow the standard treatment, the women had disease progression, and two of them died after a short time. A multidisciplinary discussion and literature review suggest that following the standard surgical procedure could be the optimal treatment to ensure mother and baby health in tongue cancer. Nonetheless choosing between maternal advantage and potential fetal damage should not be an individual medical decision. Treatment "customization" is a possibility. Patients and their families should be provided with comprehensive information and appropriate support in order to fully participate in the decision-making process. The patient's care may be improved if carried out in a specialized maternity center where the surgical oncologic treatment is managed together with the obstetric aspects.

Breast milk has always been the best source of nourishment for newborns. However, breast milk can carry a risk of infection, as it can be contaminated with bacterial or viral pathogens. This paper reviews the risk of acquisition of varicella-zoster virus (VZV) and cytomegalovirus (CMV), herpesviruses frequently detected in breastfeeding mothers, via breast milk, focusing on the clinical consequences of this transmission and the possible strategies for preventing it. Maternal VZV infections are conditions during which breastfeeding may be temporarily contraindicated, but expressed breast milk should always be given to the infant. CMV infection acquired through breast milk rarely causes disease in healthy term newborns; an increased risk of CMV disease has been documented in preterm infants. However, the American Academy of Pediatrics (AAP) does not regard maternal CMV seropositivity as a contraindication to breastfeeding; according to the AAP, in newborns weighing less than 1500 g, the decision should be taken after weighing the benefits of breast milk against the risk of transmission of infection. The real efficacy of the different methods of inactivating CMV in breast milk should be compared in controlled clinical trials, rigorously examining the negative consequences that each of these methods can have on the immunological and nutritional properties of the milk itself, with a view to establish the best risk-benefit ratio of these strategies before they are recommended for use in clinical practice.