Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.

BACKGROUND: Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS: A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION: Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.

The Management of Neonates ≥34 Weeks' Gestation at Risk of Early Onset Sepsis: A Pilot Study.

Early onset sepsis (EOS) is a potentially fatal condition in neonates, and its correct management is still challenging for neonatologists. Early antibiotic administration in the neonatal period may carry short- and long-term risks. Neonatal EOS calculator has been recently introduced as a new strategy to manage infants at risk of sepsis, and has shown promising results. METHODS: In this single-center observational retrospective study, 1000 neonates ≥ 34 weeks' gestation were enrolled with the aim to evaluate our standard protocol for the management of suspected EOS compared to the EOS calculator. Outcome measures included the following: (1) incidence of EOS and (2) proportion of infants in need of sepsis evaluations and antibiotics using our standard protocol versus theoretical application of EOS calculator. RESULTS: A total of 223/1000 infants underwent blood investigations versus 35/1000 (3.5%) if EOS calculator had been applied (p < 0.0001; k = 0.18). Furthermore, 48/1000 infants received antibiotics with our protocol versus 35/1000 with EOS calculator (p = 0.12; k = 0.58). Three infants had a positive blood culture that EOS calculator would have missed. CONCLUSIONS: In our study, EOS calculator could have reduced investigations but not antibiotic therapy. EOS calculator is an effective and promising tool, but further studies are required to improve it.

Cranial ultrasound screening in term and late preterm neonates born by vacuum-assisted delivery: Is it worthwhile?

BACKGROUND: Vacuum extraction is the most common choice to assist vaginal delivery, but there are still concerns regarding the neonatal injuries it may cause. This study aimed to evaluate the rate of intracranial injuries assessed by cranial ultrasound (cUS) among infants born by vacuum extraction, and the relationship with maternal and perinatal factors. METHODS: This was a single-center retrospective study carried out in a level-3 neonatal unit. A total of 593 term and late preterm infants born by vacuum-assisted delivery were examined with a cUS scan within 3 days after birth. RESULTS: Major head injuries were clinically silent and occurred in 2% of the infants, with a rate of intracranial haemorrhage of 1.7%. Regardless of obstetric factors, the risk of cranial injury was increased in infants requiring resuscitation at birth (p = 0.04, OR 4.1), admitted to NICU (p = 0.01, OR 5.5) or with perinatal asphyxia (p < 0.01, OR 21.3). Maternal age ≥40 years correlated both with adverse perinatal outcomes (p < 0.05) and the occurrence of major injury (p = 0.02, OR 4.6). CONCLUSION: Overall, vacuum extraction is a safe procedure for neonates. Head injuries are usually mild and asymptomatic, and with spontaneous recovery. However, the rate of major cranial injuries in our cohort warrants further investigation to support a cUS screening, particularly for infants requiring respiratory support at birth. Also, maternal age might be taken into account when evaluating the risk for neonatal complications after vacuum application.

Early Postnatal Infection of Neonates Born to Mothers Infected by SARS-CoV-2 Omicron Variant.

OBJECTIVES: To evaluate the rate of postnatal infection during the first month of life in neonates born to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive mothers during the predominant circulation of the omicron (B.1.1.529) variant. METHODS: This prospective, 10-center study enrolled mothers infected by SARS-CoV-2 at delivery and their infants, if both were eligible for rooming-in, between December 2021 and March 2022. Neonates were screened for SARS-CoV-2 RNA at 1 day of life (DOL), 2 to 3 DOL, before discharge, and twice after hospital discharge. Mother-infant dyads were managed under a standardized protocol to minimize the risk of viral transmission. Sequencing data in the study area were obtained from the Italian Coronavirus Disease 2019 Genomic platform. Neonates were included in the final analysis if they were born when the omicron variant represented >90% of isolates. RESULTS: Eighty-two percent (302/366) of mothers had an asymptomatic SARS-CoV-2 infection. Among 368 neonates, 1 was considered infected in utero (0.3%), whereas the postnatal infection rate during virtually exclusive circulation of the omicron variant was 12.1%. Among neonates infected after birth, 48.6% became positive during the follow-up period. Most positive cases at follow-up were detected concurrently with the peak of coronavirus disease 2019 cases in Italy. Ninety-seven percent of the infected neonates were asymptomatic. CONCLUSIONS: The risk of early postnatal infection by the SARS-CoV-2 omicron variant is higher than that reported for previously circulating variants. However, protected rooming-in practice should still be encouraged given the paucity of symptoms in infected neonates.

Breastfeeding and human milk bank in a neonatal intensive care unit: impact of the COVID-19 pandemic in an Italian cohort of very low birth weight infants.

BACKGROUND: Parental stress in neonatal intensive care units (NICU) is well known, as is the stress induced by the COVID-19 pandemic. This combination might increase stress to the extent of affecting the availability of maternal expressed milk and the success of establishing breastfeeding. This is particularly relevant in very preterm infants. METHODS: We conducted a single-centre retrospective analysis in two cohorts of very low birth weight infants born in a hospital in Italy. Babies born before the pandemic (September 2017 - December 2019) (n = 101) and during the pandemic (March 2020 - December 2021) (n = 67) were included in the analysis. We compared the rate of babies fed with maternal milk (both expressed and / or donated) at the achievement of full enteral feeding and the rate of those exclusively breastfed at discharge in the two groups. Then, we analysed the impact of donated human milk availability on infant formula use. We also compared mother's need for psychological support during NICU stay and the duration of psychological follow-up after discharge. RESULTS: In our NICU the availability of expressed maternal milk significantly decreased during the COVID-19 pandemic (86.1% before the pandemic vs 44.8% during the pandemic, p < 0.001) at the time of full enteral feeding achievement. Thanks to the availability of donated human milk, the rate of formula-fed babies remained almost unchanged (13.9% vs 14.9%). At discharge, the rate of breastfeeding was similar (73.3% vs 72.7%). The maternal need for psychological support was significantly higher during the pandemic (33% vs 64%, p < 0.001), as well as the duration of follow-up > 6 months (1% vs 15%, p < 0.001). No differences in the main clinical outcomes were found. CONCLUSION: Pandemic-induced stress had a significant impact on the availability of expressed maternal milk in NICU. However, the presence of human donated milk was fundamental in preventing increased use of infant formula during NICU stays. This underlines how strategies to implement the widespread establishment of donor milk banks on a national level are warranted. Further research is desirable to optimise the use of donated human milk banks during emergency situations.

Human parechovirus type 5 neurological infection in a neonate with a favourable outcome: A case report.

The majority of parechovirus A type 5 (PeV-A5) infections have been reported in patients with gastrointestinal syndromes. In contrast, a sepsis-like illness associated with PeV-A5 infection has been reported only anecdotally. Herein, we report the first case in Italy of a PeV-A5 neurological infection presenting in a neonate with a sepsis-like syndrome. The patient, a healthy male infant born at 41 weeks of gestation, was highly distressed and inconsolable, and had been crying persistently, with poor breastfeeding, since the previous day. From day 2 to day 4, the newborn was feverish with mild irritability; breastfeeding was preserved and regularly supported. His clinical condition progressively improved, with defervescence on day 4. He was discharged after 7 days, and neurological examination results indicated only mild impairment in visual fixation and vertical eye tracking and mild axial hypotonia. The Italian PeV-A5 strain was phylogenetically related to three strains detected in Denmark in 2012, as well as to one detected in Australia and one in Greece in 2015, with an average nucleotide identity of 97.9% (range 95.9-100.0%). Enterovirus/PeV infection in the newborn should be ruled out in cases of infants with unexplained fever and/or a sepsis-like syndrome and/or meningoencephalitis. An aetiological diagnosis is essential to avoid the unnecessary administration of antibiotics and to plan long-term follow-up until schooling.

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a ß-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration  The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Introducing complementary foods in the first year of life.

Introduction of solid foods is a fundamental step in the development of an individual. There are many implications that weaning contains not only on a nutritional plan, but also on the contingent and long-term health of an individual. Over time this nutritional passage has evolved through the acquisition of new knowledge about maturation of anatomical and neurosensory structures involved in all the phases of such a complex process. The understanding of a maturing taste of infant and cultural changes is another key to understand the evolution of introduction of solid foods in infants. What is contained in this text encapsulates thus the evolutionary path of weaning in recent years, showing current trends in the light of cultural changes and new scientific acquisitions.

Nutritional and metabolic programming during the first thousand days of life.

The latest scientific acquisitions are demonstrating what has already been hypothesized for more than twenty years about the development of the state of health/illness of individuals. Indeed, certain stimuli, if applied to a sensible phase of development, are able to modify, through epigenetic mechanisms, gene expression of DNA, resulting in adaptive modifications of phenotype to the environment, which may reflect negatively on the health of every individual. This concept, applied to nutrition, has opened up important prospects for research in this area. The nutritional history of an individual, linked to the development of a healthy state, would begin very early. In fact, since the pregnancy and for the next two years (for a total of about 1000 days), the maternal eating habits, the type of breastfeeding and then the main stages of nutrition in the evolutionary phase represent those sensitive moments, essential for the development of important endocrine, metabolic, immunological alterations, better known as metabolic syndrome. This condition would represent the physiopathogenetic basis for explaining a series of disorders, known as non communicable diseases (NCDs) such as obesity, diabetes, hypertension, cardiovascolar disease and all those conditions that today affect the health of most industrialized countries and through the years are emerging especially in developing countries (South America, Asia), where new environmental conditions and increased food availability are changing food habits, with far-reaching public health impacts. This paper analyzes these new nutritional perspectives and the main implications of what has been termed the 1000-day theory.