SARS-CoV-2 perinatal transmission and neonatal outcomes across four different waves of COVID-19 pandemic: A nationwide prospective cohort study from the Italian Society of Neonatology.

OBJECTIVES: To describe how SARS-CoV-2 infection at the time of delivery affected maternal and neonatal outcomes across four major waves of the COVID-19 pandemic in Italy. METHODS: This is a large, prospective, nationwide cohort study collecting maternal and neonatal data in case of maternal peripartum SARS-CoV-2 infection between February 2020 and March 2022. Data were stratified across the four observed pandemic waves. RESULTS: Among 5201 COVID-19-positive mothers, the risk of being symptomatic at delivery was significantly higher in the first and third waves (20.8-20.8%) than in the second and fourth (13.2-12.2%). Among their 5284 neonates, the risk of prematurity (gestational age <37 weeks) was significantly higher in the first and third waves (15.6-12.5%). The risk of intrauterine transmission was always very low, while the risk of postnatal transmission during rooming-in was higher and peaked at 4.5% during the fourth wave. A total of 80% of positive neonates were asymptomatic. CONCLUSION: The risk of adverse maternal and neonatal outcomes was significantly higher during the first and third waves, dominated by unsequenced variants and the Delta variant, respectively. Postnatal transmission accounted for most neonatal infections and was more frequent during the Omicron period. However, the paucity of symptoms in infected neonates should lead us not to separate the dyad.

Minipuberty in Male Full-term Neonates Appropriate and Small for Gestational Age and in Preterm Babies: Data From a Single Centre.

Objective: The postnatal activation of the hypothalamic-pituitary-gonadal(HPG) axis is usually known as "minipuberty". There are still open questions on its biological activity and significance depending on sex, gestational age(GA) and birth weight(BW) with few longitudinal data. Methods: Single-centre longitudinal study to quantify urinary FSH(uFSH), LH(uLH) and testosterone(uTs) in male neonates. 46 neonates were enrolled and sorted into 3 subgroups: 23 full-term boys appropriate for GA(FT AGA), 11 full-term boys with BW≤3 rd centile(FT SGA), and 12 preterm(PT) boys≤33 weeks of GA. Urinary hormones were measured with electrochemiluminescence immunoassay and correlated to simultaneous auxological parameters, linear growth and external genitalia at scheduled time-points. Results: PT boys display a pulsatile pattern of urinary gonadotropins(uGns) with higher levels of uLH and a gradual increase of uTs. Testicular descent starts from 29-32weeks with the peak of uTs. During the first 12-months post term age(PTA), FT AGA boys display a better linear growth(p<0.05). PT show higher uGns levels until 3-months PTA. Considering chronological age, PT babies in the first 90 days of life have higher uLH levels than FT AGA with a peak at 7 and 30 days(p<0.001) and higher uTs levels. Correlation analysis between penile growth of all neonates and uTs is significant(p=0.04) but not when subgrouping. Conclusions: This study provides valuable information on the postnatal HPG axis activation in term and preterm infants. Minipuberty may involve an early window of opportunity to evaluate the HPG axis functionality. Further studies with a long-term follow-up are needed with a special focus on possible consequences of GA and BW.

Progressive osseous heteroplasia: A case report with an unexpected trigger.

Progressive osseous heteroplasia (POH) is a rare genetic disorder characterised by progressive heterotopic ossification (HO) within the skin and subcutaneous tissues. The condition is caused by heterozygous inactivating mutations of the GNAS gene and usually presents in infancy. We describe the case of a white male ex-preterm who was first referred because of subcutaneous calcium deposits along the right arm after extravasation of parenteral nutrition. As these lesions progressed, a skin biopsy was undertaken which revealed intramembranous ossification. Genetic testing revealed a constitutional, de novo, heterozygous, nonsense variant in the GNAS gene that has not previously been described, but which is consistent with patient's clinical diagnosis of POH. No endocrine abnormalities or other signs congruent with overlapping conditions were detected. To the best of our knowledge, this is the first case describing an inflammatory trigger in POH. Trials with intravenous bisphosphonate and glucocorticoid as well as with topical sodium thiosulphate were attempted without clinical improvement. Excision of the calcifications and physiotherapy seem to have provided a partial improvement on mobility of the elbow. This case widens the spectrum of phenotypes seen in GNAS mutation disorders and suggests that alternative anti-inflammatory treatments may be effective. Mutations in GNAS should be considered in cases of significant progressive calcium deposition after extravasation injury.

Parents' Experience in an Italian NICU Implementing NIDCAP-Based Care: A Qualitative Study.

Background: The birth of a preterm infant and his/her immediate admittance to the Neonatal Intensive Care Unit (NICU) are sudden, unexpected, stressful and painful events for parents. In the last decade, in response to the increased awareness of the stressful experiences of parents, much attention has been paid to Family-Centered Care (FCC) and the implementation of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP). According to the NIDCAP model, the infant-parents' dyad is the core of the care provided by the NICU professionals to reduce the stress experienced by parents. So far, the literature does not show a clear correlation between parental experiences and the NICU practices according NIDCAP principles. Aims: To explore how parents of preterm infants experienced the NIDCAP-based care from admission to discharge, in particular, their relationships with NICU professionals and with other parents, and the organization of the couple's daily activities during this process. Design: Qualitative exploratory study. Methods: Twelve parents of preterm infants born between January 2018 and December 2020 at the NICU of Modena, with a gestational age at birth of less than 30 weeks and/or a birth weight of less than 1250 g, were recruited. Three couples had twins, and the total number of infants was 15. All infants were followed for up to 24 months post-term age (PTA) for neurological outcomes. Each couple was given a semi-structured online interview about their experience during their infant's hospitalization in the NICU up to discharge. The interview was developed around three time points: birth, hospitalization and discharge. The data analysis was conducted according to the template analysis method. Results: The admission to the NICU was unexpected and extraordinary, and its impact was contained by the skilled staff who were capable of welcoming the parents and making them feel they were involved and active collaborators in the care of their infant. The emotional experience was compared to being in a blender; they were overwhelmed by changing emotions, ranging from terrible fear to extreme joy. The couple's activities of daily life were reorganized after the infant's birth and admission to the NICU. Fathers felt unbalanced and alone in taking care of their partners and their children. Conclusions: This is the first study in Italy to explore parental experience in an NICU implementing NIDCAP-based care. The NIDCAP approach in the NICU of Modena helps parents to be involved early, to develop parental skills, and to be prepared for the transition home; and it also facilitates and enhances the relationship between parents and NICU staff.

Unexpected Vertical Transmission of SARS-CoV-2: Discordant Clinical Course and Transmission from Mother to Newborn.

Mother-to-newborn COVID-19 transmission is mainly postnatal, but single-case reports and small case series have also described SARS-CoV-2 transplacental transmission. Unfortunately, studies regarding vertical transmission of SARS-CoV-2 lack systematic approaches to diagnosis and classification. So far, scientific evidence seems to suggest that the severity of maternal infection increases the risk of vertical transmission. We report two neonates born from COVID-19-positive mothers, of which one of the newborns had a vertical infection. The placental involvement, and consequent intrauterine transmission of SARS-CoV-2, were inversely related to the severity of the maternal disease. The description of cases divergent from current evidence on this topic could provide new insights to better understand SARS-CoV-2 vertical transmission.

Should we give antibiotics to neonates with mild non-progressive symptoms? A comparison of serial clinical observation and the neonatal sepsis risk calculator.

Objective: To compare two strategies [the neonatal sepsis risk calculator (NSC) and the updated serial clinical observation approach (SCO)] for the management of asymptomatic neonates at risk of early-onset sepsis (EOS) and neonates with mild non-progressive symptoms in the first hours of life. Methods: This was a single-center, retrospective cohort study conducted over 15 months (01/01/2019-31/03/2020). All live births at ≥34 weeks of gestation were included. Infants were managed using SCO and decisions were compared with those retrospectively projected by the NSC. The proportion of infants recommended for antibiotics or laboratory testing was compared in both strategies. McNemar's non-parametric test was used to assess significant differences in matched proportions. Results: Among the 3,445 neonates (late-preterm, n = 178; full-term, n = 3,267) 262 (7.6%) presented with symptoms of suspected EOS. There were no cases of culture-proven EOS. Only 1.9% of the neonates were treated with antibiotics (median antibiotic treatment, 2 days) and 4.0% were evaluated. According to NSC, antibiotics would have been administered in 5.4% of infants (absolute difference between SCO and NSC, 3.51%; 95% CI, 3.14-3.71%; p <0.0001) and 5.6% of infants would have undergone "rule out sepsis" (absolute difference between SCO and NSC, 1.63%, 95% CI 1.10-2.05; p <0.0001). Conclusion: SCO minimizes laboratory testing and unnecessary antibiotics in infants at risk of EOS or with mild non-progressive symptoms, without the risk of a worse neonatal outcome. The NSC recommends almost three times more antibiotics than the SCO without improving neonatal outcomes.

Enteroviral Infections in the First Three Months of Life.

Enteroviruses (EVs) are an important source of infection in the paediatric age, with most cases concerning the neonatal age and early infancy. Molecular epidemiology is crucial to understand the circulation of main serotypes in a specific area and period due to their extreme epidemiological variability. The diagnosis of EVs infection currently relies on the detection of EVs RNA in biological samples (usually cerebrospinal fluid and plasma, but also throat swabs and feces) through a polymerase chain reaction assay. Although EVs infections usually have a benign course, they sometimes become life threatening, especially when symptoms develop in the first few days of life. Mortality is primarily associated with myocarditis, acute hepatitis, and multi-organ failure. Neurodevelopmental sequelae have been reported following severe infections with central nervous system involvement. Unfortunately, at present, the treatment of EVs infections is mainly supportive. The use of specific antiviral agents in severe neonatal infections has been reported in single cases or studies including few neonates. Therefore, further studies are needed to confirm the efficacy of these drugs in clinical practice.

Can Fraction of Inspired Oxygen Predict Extubation Failure in Preterm Infants?

BACKGROUND: Prolonged mechanical ventilation in preterm infants may cause complications. We aimed to analyze the variables affecting extubation outcomes in preterm infants at high risk of extubation failure. METHODS: This was a single-center, observational, retrospective study. Extubation failure was defined as survival with the need for reintubation within 72 h. Successfully extubated neonates (group 1) were compared to those with failed extubation (group 2). Multivariate logistic regression analysis evaluated factors that predicted extubation outcomes. RESULTS: Eighty infants with a birth weight under 1000 g and/or gestational age (GA) under 28 weeks were included. Extubation failure occurred in 29 (36.2%) and success in 51 (63.8%) neonates. Most failures (75.9%) occurred within 24 h. Pre-extubation inspired oxygen fraction (FiO2) of 27% had a sensitivity of 58.6% and specificity of 64.7% for extubation failure. Post-extubation FiO2 of 32% had a sensitivity of 65.5% and specificity of 62.8% for failure. Prolonged membrane rupture (PROM) and high GA were associated with extubation success in multivariate logistic regression analysis. CONCLUSIONS: High GA and PROM were associated with extubation success. Pre- and post-extubation FiO2 values were not significantly predictive of extubation failure. Further studies should evaluate if overall assessment, including ventilatory parameters and clinical factors, can predict extubation success in neonates.

Subtle impairment of neurodevelopment in infants with late fetal growth restriction.

INTRODUCTION: Children with late fetal growth restriction (FGR) are at high risk of being born small for gestational age (SGA). These categories of newborns are at increased risk for neurodevelopment impairment. The general movements assessment, in particular at fidgety age, has been used to predict neurological dysfunctions. This study aimed to evaluate growth recovery, presence of fidgety movements at 3 months, and neurodevelopmental outcome at 2 years of age in term late FGR infants and adequate for gestational age (AGA) controls. METHODS: Prospective clinical evaluation. At 3 months auxological parameters (AP) and neurological examination were evaluated while at 24 months neurodevelopment outcome by Griffiths Mental Development Scales (GMDS-R) was evaluated. RESULTS: 38 late FGR and 20 AGA controls completed the study. Despite a significant catch up, at 3 months 13% of late FGR presented at least one auxological parameter <3° percentile. Moreover, 23.7% of late FGR infants did not show fidgety movements compared to 100% AGA controls (p < .001). Cranial circumference at birth resulted a positive predictive factor for FMs (p = .039). At 2 years of age, a difference statistically significant between late FGR and AGA was detected in GMDS-R. CONCLUSION: Independently from growth recovery, fidgety movements resulted less expressed in late FGR infants, and at 2 years of age the neurodevelopmental assessment revealed differences in each domain of evaluation between late FGR and AGA infants, although within normal ranges.

Clinical utility of urinary gonadotrophins in hypergonadotrophic states as Turner syndrome.

Background Girls with Turner syndrome (TS) are at an increased risk of primary ovarian insufficiency (POI). Good correlation between serum and urinary gonadotrophins exists in children assessed for disorders of puberty, but there is little evidence of their reliability in hypergonadotropic states. Objectives To determine whether there was a correlation between serum and urinary Luteinising Hormone (uLH) and Follicle-Stimulating Hormone (uFSH) in hypergonadotrophic states, and whether uFSH could suggest an ovarian failure in TS as Anti-Mullerian Hormone (AMH). Patients and Methods Retrospective cohort study of 37 TS girls attending the paediatric TS clinic in Glasgow between February 2015 and January 2019, in whom 96 non-timed spot urine samples were available with a median age at time of sample of 12.89 years (3.07-20.2 years). uLH and uFSH were measured by chemiluminescent microparticle immunoassay. Simultaneous serum gonadotrophins and AMH were available in 30 and 26 girls, respectively. AMH <4 pmol/L was considered indicative of ovarian failure. Results A strong correlation was found between serum LH and uLH (r 0.860, P<0.001) and serum FSH and uFSH (r 0.905, p<0.001). Among patients≥10 years not on oestrogen replacement, ROC curve identified uFSH as a reasonable marker for AMH<4 pmol/L uFSH of >10.85 U/L indicates an AMH <4 pmol/L with 75% sensitivity and 100 % specificity (AUC 0.875)with similar ability as serum FSH (AUC 0.906). Conclusion uLH and uFSH are non-invasive, useful and reliable markers of ovarian activity in hypergonadotropic states as TS. uFSH could provide an alternative to AMH (in centres which are limited by availability or cost) in revealing ovarian failure and requirement for oestrogen replacement in pubertal induction.

Health-related quality of life and metabolic control in immigrant and Italian children and adolescents with type 1 diabetes and in their parents.

OBJECTIVE: To determine if the diabetes-specific health-related quality of life (D-HRQOL) of young people with type 1 diabetes (T1D) and their parents is influenced by migrant status. SUBJECTS AND METHODS: One hundred and twenty-five patients (12.4 ± 3.55 years, males 53.6%) with T1D and their parents (102 mothers, 37 fathers) were enrolled and categorized into: group A (both foreign parents) and group B (both native Italian parents). The Pediatric Quality of Life Inventory™ 3.0 Diabetes Module (PedsQL™ 3.0 DM) was used to evaluate the D-HRQOL. Data on diabetic ketoacidosis (DKA) at T1D onset, insulin therapy, and glycosylate hemoglobin (HbA1c) were also collected. RESULTS: Group A (n = 40), compared to group B (n = 85), had higher frequency of DKA at T1D onset (P < .001) and a lower use of sensor augmented insulin pump (P = .015). HbA1c values were higher in group A than in group B (P < .001). Patients' "Diabetes symptoms" (P = .004), "Treatment barriers" (P = .001), and "Worry" (P = .009) scales scores were lower in group A than in group B. Mothers of group A had lower scores in "Diabetes symptoms" (P = .030), "Treatment barriers" (P < .001), "Treatment adherence" (P = .018), "Communication" (P = .009) scales, and total score (P = .011) compared to the group B ones. High PedsQL™ 3.0 DM was significantly associated with being Italian, being prepubertal, and having lower HbA1c mean levels. CONCLUSIONS: Being a migrant confers disadvantages in terms of D-HRQOL and metabolic control in children and adolescents with T1D. Specific educational interventions should be considered in the clinical care of patients with migration background, to improve D-HRQOL and health status.

Neuroprem: the Neuro-developmental outcome of very low birth weight infants in an Italian region.

INTRODUCTION: The survival of preterm babies has increased worldwide, but the risk of neuro-developmental disabilities remains high, which is of concern to both the public and professionals. The early identification of children at risk of neuro-developmental disabilities may increase access to intervention, potentially influencing the outcome. AIMS: Neuroprem is an area-based prospective cohort study on the neuro-developmental outcome of very low birth weight (VLBW) infants that aims to define severe functional disability at 2 years of age. METHODS: Surviving VLBW infants from an Italian network of 7 neonatal intensive care units (NICUs) were assessed for 24 months through the Griffiths Mental Developmental Scales (GMDS-R) or the Bayley Scales of Infant and Toddler Development (BSDI III) and neuro-functional evaluation according to the International Classification of Disability and Health (ICF-CY). The primary outcome measure was severe functional disability at 2 years of age, defined as cerebral palsy, a BSDI III cognitive composite score < 2 standard deviation (SD) or a GMDS-R global quotients score < 2 SD, bilateral blindness or deafness. RESULTS: Among 211 surviving VLBW infants, 153 completed follow-up at 24 months (72.5%). Thirteen patients (8.5%) developed a severe functional disability, of whom 7 presented with cerebral palsy (overall rate of 4.5%). Patients with cerebral palsy were all classified with ICF-CY scores of 3 or 4. BSDI III composite scores and GMDS-R subscales were significantly correlated with ICF-CY scores (p < 0.01). CONCLUSION: Neuroprem represents an Italian network of NICUs aiming to work together to ensure preterm neuro-developmental assessment. This study updates information on VLBW outcomes in an Italian region, showing a rate of cerebral palsy and major developmental disabilities in line with or even lower than those of similar international studies. Therefore, Neuroprem provides encouraging data on VLBW neurological outcomes and supports the implementation of a preterm follow-up programme from a national network perspective.

Minipuberty: Looking Back to Understand Moving Forward.

Hypothalamic-pituitary-gonadal (HPG) axis activation occurs three times in life: the first is during fetal life, and has a crucial role in sex determination, the second time is during the first postnatal months of life, and the third is with the onset of puberty. These windows of activation recall the three windows of the "Developmental Origin of Health and Disease" (DOHaD) paradigm and may play a substantial role in several aspects of human development, such as growth, behavior, and neurodevelopment. From the second trimester of pregnancy there is a peak in gonadotropin levels, followed by a decrease toward term and complete suppression at birth. This is due to the negative feedback of placental estrogens. Studies have shown that in this prenatal HPG axis activation, gonadotropin levels display a sex-related pattern which plays a crucial role in sex differentiation of internal and external genitalia. Soon after birth, there is a new increase in LH, FSH, and sex hormone concentrations, both in males and females, due to HPG re-activation. This postnatal activation is known as "minipuberty." The HPG axis activity in infancy demonstrates a pulsatile pattern with hormone levels similar to those of true puberty. We review the studies on the changes of these hormones in infancy and their influence on several aspects of future development, from linear growth to fertility and neurobehavior.

Intrapartum beta-lactam antibiotics for preventing group B streptococcal early-onset disease: can we abandon the concept of 'inadequate' intrapartum antibiotic prophylaxis?

Introduction: Neonatal sepsis remains a serious and potentially fatal illness. Intrapartum antibiotic prophylaxis (IAP) prevents group B streptococcal (GBS) early-onset sepsis. The optimal duration of IAP (adequate IAP) to reduce vertical transmission of GBS has been debated. Understanding the mechanism of action of IAP may help in minimizing neonatal evaluation and unnecessary antibiotic use.Areas covered: In recent years, several studies on pharmacokinetics and clinical use of IAP have been published. Although penicillin and ampicillin are the most preferred antibiotics, the clinical efficacy of non-beta-lactam antibiotics, including clindamycin and vancomycin, used in cases of penicillin anaphylaxis-associated allergy, remains debatable. This is a narrative review of the literature regarding the impact of 'inadequate' IAP on the clinical management of women and newborns.Expert opinion: Recent evidence suggests that 'inadequate' IAP with beta-lactams is more effective in preventing vertical transmission of GBS than previously thought. Newborns exposed to intrapartum beta-lactams and who are asymptomatic at birth are likely uninfected, irrespective of IAP duration before delivery. Hence, we may abandon the concept of 'inadequate' IAP with beta-lactams in early-onset GBS sepsis, relying primarily on clinical signs observed at birth for managing IAP-exposed neonates.

Clinical characterization of neonatal and pediatric enteroviral infections: an Italian single center study.

BACKGROUND: Enteroviruses (EVs) are an important cause of illness, especially in neonates and young infants. Clinical and laboratory findings at different ages, brain imaging, and outcomes have been inadequately investigated. METHODS: We retrospectively investigated EV infections occurring at an Italian tertiary care center during 2006-2017. Cases were confirmed with a positive polymerase chain reaction on blood or cerebrospinal fluid. Clinical and laboratory findings according to age at presentation were analyzed. RESULTS: Among 61 cases of EV infection, 56 had meningitis, 4 had encephalitis, and 1 had unspecific febrile illness. Forty-seven cases (77.0%) presented at less than 1 year of age, and most were less than 90 days of age (n = 44). Presentation with fever (p < 0.01), higher median temperature (p < 0.01), and irritability (p < 0.01) were significantly more common among infants aged less than 90 days, who also had significantly higher peak temperatures during the course of the disease (p < 0.01). In contrast, gastrointestinal symptoms were more common in infants and children aged over 90 days (p = 0.02). Only 4 of 61 infections (6.5%) were severe and all affected younger infants (p < 0.01). CONCLUSIONS: We detail epidemiological, clinical, and laboratory findings in a cohort of 61 children. Infants aged less than 90 days have more severe disease; they are more likely to present with fever, higher median temperature, and irritability and less likely to develop gastrointestinal symptoms.

Two Overlapping Clusters of Group B Streptococcus Late-onset Disease in a Neonatal Intensive Care Unit.

OBJECTIVES: Current predominant routes of group B Streptococcus (GBS) transmission in preterm neonates admitted to neonatal intensive care unit (NICU) are poorly defined. We report 2 overlapping clusters of GBS late-onset disease (LOD) from June to September 2015 in an Italian NICU. METHODS: During the outbreak, possible sources of transmission (equipment, feeding bottles and breast pumps) were swabbed. Specimens from throat and rectum were collected on a weekly basis from all neonates admitted to NICU. Colonized or infected neonates had cohorting. Bacterial isolates were characterized by serologic and molecular typing methods. RESULTS: GBS was isolated in 2 full-term and 7 preterm neonates. Strains belonged to serotype III, with 3 different sequence types (ST17, ST182 and ST19). Full-term neonates were colonized with GBS strains unrelated to the clusters (ST182 and ST19). Two distinct ST17 strains caused 2 clusters in preterm neonates: a first cluster with 1 case of LOD and a second, larger cluster with 6 LOD in 5 neonates (one of them had recurrence). ST17 strains were isolated from vaginorectal and milk samples of 2 mothers. Two preterm neonates had no evidence of colonization for weeks, until they presented with LOD. CONCLUSIONS: Molecular analyses identified the presence of multiclonal GBS strains and 2 clusters of 7 cases of GBS-LOD. The dynamics of transmission of GBS within the NICU were complex. Breast milk was suspected to be one of the possible sources. In a research setting, the screening of GBS carrier mothers who deliver very preterm could contribute to the tracking of GBS transmission.