Milrinone in persistent pulmonary hypertension of newborn: a scoping review.

Persistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition in newborns admitted to the neonatal intensive care units (NICUs). PPHN has still a high mortality and morbidity. Inhaled nitric oxide (iNO) is the first line vasodilator therapy for PPHN in high income countries. In low-to-middle income countries (LMICs), availability of iNO remains scarce and expensive. The purpose of this scoping review was to evaluate the current existing literature for milrinone therapy in PPHN and to identify the knowledge gaps in milrinone use in infants with PPHN. The available evidence for milrinone remains limited both as monotherapy and as an adjuvant to iNO. The studies were heterogeneous, conducted in different settings, with different populations and more importantly the endpoints of these trials were short-term outcomes such as changes in oxygenation and blood pressure. Large prospective studies investigating long-term outcomes, mortality, and the need for Extracorporeal membrane oxygenation (ECMO) are warranted. Randomized controlled trials with milrinone as monotherapy are needed in LMICs where iNO availability remains limited. IMPACT: Milrinone has a potential role in the management of PPHN both as an adjuvant to iNO as well as a monotherapy. This scoping review identified the problems existing in the published literature on milrinone and the barriers to generalization of these results. Multi-centre randomized controlled trials on milrinone, especially involving centers from low- and middle-income countries are needed, where it can be evaluated as first-line pulmonary vasodilator therapy.

D-Bifunctional Protein Deficiency Diagnosis-A Challenge in Low Resource Settings: Case Report and Review of the Literature.

D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.

The Early Hematological Profile and Its Variations: A Useful Tool in the Prediction of Intraventricular Hemorrhage in Extremely Preterm Infants.

Background and Objectives: The purpose of this study to investigate if the early variations in the hematological profile could be a useful tool in the prediction and evaluation of intraventricular hemorrhage. Materials and Methods: It is a retrospective study conducted between 1 January 2017 and 31 December 2022, in a tertiary academic center. In-born infants ≤ 28 weeks of gestation (n = 134) were enrolled. The study group of infants with all grades of IVH was further divided into mild IVH subgroups (grades 1 and 2) and severe IVH subgroups (grades 3 and 4); the control group included infants without IVH. Results: The prevalence of IVH was 35.8% (n = 48 of 134 infants-study group). We identified significantly lower median values of HGB (p = 0.0312) and HCT (p = 0.0172) in all grades of the IVH group at birth as compared with control, followed by a significantly higher drop in MCV (p = 0.0146) and MCH (p = 0.0002) in the fourth day of life. Conclusions: Extremely preterm infants with IVH may have lower HTC and HGB values at birth, together with a decrease in MCH and MCHC and increase in MPV. The predictive model based on logistic regression analysis could predict the probability of the occurrence of IVH according to their values.

Updated Clinical Practice Guidelines in Resuscitation and the Management of Respiratory Distress Syndrome in Extremely Preterm Infants during Two Epochs in Romania: Impact on Outcomes.

BACKGROUND: Adequate perinatal management is essential in caring for extremely preterm (EP) infants. We aimed to evaluate and compare the impact of different protocols on short-term outcomes. METHODS: A retrospective study was conducted on EP infants in a Romanian perinatal tertiary center during 2008-2012 and 2018-2022. RESULTS: Data on 270 EP infants (121 in period I, 149 in period II) were analyzed collectively and stratified into two subgroups by gestational age. Initial FiO2 administration (100% vs. 40%% p < 0.001), lung recruitment at birth (19.0% vs. 55.7% p < 0.001), early rescue surfactant administration (34.7% vs. 65.8%; p < 0.001), and the mechanical ventilation rate (98.3% vs. 58.4%; p < 0.001) were significantly improved during period II. Survival rates of EP infants significantly improved from 41.3% to 72.5%, particularly in the 26-28 weeks subgroup (63.8% to 83%). Compared to period I, the overall frequency of severe IVH decreased in period II from 30.6% to 14.1%; also, BPD rates were lower (36.6% vs. 23.4%; p = 0.045) in the 26-28 weeks subgroup. Despite improvements, there were no significant differences in the frequencies of NEC, sepsis, PVL, ROP, or PDA. CONCLUSIONS: Implementing evidence-based clinical guidelines can improve short-term outcomes.

Identification of the Best Predictive Model for Mortality in Outborn Neonates-Retrospective Cohort Study.

BACKGROUND: Transportation of sick newborns is a major predictor of outcome. Prompt identification of the sickest newborns allows adequate intervention and outcome optimization. An optimal scoring system has not yet been identified. AIM: To identify a rapid, accurate, and easy-to-perform score predictive for neonatal mortality in outborn neonates. MATERIAL AND METHODS: All neonates admitted by transfer in a level III regional neonatal unit between 1 January 2015 and 31 December 2021 were included. Infants with congenital critical abnormalities were excluded (N = 15). Gestational age (GA), birth weight (BW), Apgar score, place of birth, time between delivery and admission (AT), early onset sepsis, and sick neonatal score (SNS) were collected from medical records and tested for their association with mortality, including in subgroups (preterm vs. term infants); GA, BW, and AT were used to develop MSNS-AT score, to improve mortality prediction. The main outcome was all-cause mortality prediction. Univariable and multivariable analysis, including Cox regression, were performed, and odds ratio and hazard ratios were calculated were appropriate. RESULTS: 418 infants were included; 217/403 infants were born prematurely (53.8%), and 20 died (4.96%). Compared with the survivors, the non-survivors had lower GA, BW, and SNS scores (p < 0.05); only the SNS scores remained lower in the subgroup analysis. Time to admission was associated with an increased mortality rate in the whole group and preterm infants (p < 0.05). In multiple Cox regression models, a cut-off value of MSNS-AT score ≤ 10 was more precise in predicting mortality as compared with SNS (AUC 0.735 vs. 0.775) in the entire group and in the preterm infants group (AUC 0.885 vs. 0.810). CONCLUSIONS: The new MSNS-AT score significantly improved mortality prediction at admission in the whole study group and in preterm infants as compared with the SNS score, suggesting that, besides GA and BW, AT may be decisive for the outcome of outborn preterm infants.

Impact of SARS-CoV-2 Infection on Maternal and Neonatal Outcome in Correlation with Sociodemographic Aspects: A Retrospective Case-Control Study.

BACKGROUND: As the COVID-19 pandemic evolved, concerns grew about its impact on pregnant women. This study aimed to determine how SARS-CoV-2 affects pregnancy, birth, and newborns, in order to identify vulnerable individuals and provide proper care. METHODS: This is a retrospective case-control study of 398 pregnant women who delivered at the Emergency Clinical County Hospital in Sibiu, Romania from 1 February 2020 to 31 March 2022. Patients were initially grouped and compared based on their RT-PCR SARS-CoV-2 test results into the COVID group (cases) (N = 199) and non-COVID group (control) (N = 199). The COVID cases were further divided and compared according to the pre-Delta (N = 105) and Delta/Omicron (N = 94) SARS-CoV-2 variants. COVID cases and control groups were compared to identify correlations between sociodemographic factors, pregnancy outcomes, and SARS-CoV-2 infection. The same comparisons were performed between pre-Delta and Delta/Omicron groups. RESULTS: There were no significant differences concerning maternal residence, while educational level and employment proportion were higher among the positively tested patients. No significant differences were found for neonatal and pregnancy complications between COVID cases and control groups. Except for a lower mean gestational age, no significant differences were found between pre-Delta and Delta/Omicron periods. The maternal mortality in the infected group was 0.5% (1 case). CONCLUSIONS: Our study showed that SARS-CoV-2 infection at birth did not significantly affect maternal and neonatal outcomes, not even considering the SARS-CoV-2 strain.

A Decision-Tree Approach to Assist in Forecasting the Outcomes of the Neonatal Brain Injury.

Neonatal brain injury or neonatal encephalopathy (NE) is a significant morbidity and mortality factor in preterm and full-term newborns. NE has an incidence in the range of 2.5 to 3.5 per 1000 live births carrying a considerable burden for neurological outcomes such as epilepsy, cerebral palsy, cognitive impairments, and hydrocephaly. Many scoring systems based on different risk factor combinations in regression models have been proposed to predict abnormal outcomes. Birthweight, gestational age, Apgar scores, pH, ultrasound and MRI biomarkers, seizures onset, EEG pattern, and seizure duration were the most referred predictors in the literature. Our study proposes a decision-tree approach based on clinical risk factors for abnormal outcomes in newborns with the neurological syndrome to assist in neonatal encephalopathy prognosis as a complementary tool to the acknowledged scoring systems. We retrospectively studied 188 newborns with associated encephalopathy and seizures in the perinatal period. Etiology and abnormal outcomes were assessed through correlations with the risk factors. We computed mean, median, odds ratios values for birth weight, gestational age, 1-min Apgar Score, 5-min Apgar score, seizures onset, and seizures duration monitoring, applying standard statistical methods first. Subsequently, CART (classification and regression trees) and cluster analysis were employed, further adjusting the medians. Out of 188 cases, 84 were associated to abnormal outcomes. The hierarchy on etiology frequencies was dominated by cerebrovascular impairments, metabolic anomalies, and infections. Both preterms and full-terms at risk were bundled in specific categories defined as high-risk 75-100%, intermediate risk 52.9%, and low risk 0-25% after CART algorithm implementation. Cluster analysis illustrated the median values, profiling at a glance the preterm model in high-risk groups and a full-term model in the inter-mediate-risk category. Our study illustrates that, in addition to standard statistics methodologies, decision-tree approaches could provide a first-step tool for the prognosis of the abnormal outcome in newborns with encephalopathy.

Overview of the pediatric healthcare system in Romania.

Until 1989, Romania was one of the countries of the communist bloc in Europe and its healthcare system was characterized by centralized planning and severe underfunding, with low performance and low quality healthcare. Since 1998, Romania replaced the Semashko model with a social health insurance system, highly centralized under the management of the Ministry of Health as the central administrative authority. After joining the European Union, quality of life increased in our country and there were efforts to improve the quality of healthcare, including pediatric and neonatal care. Still, Romania has the lowest share of health expenditure of gross domestic product among the European Union Member States and the lowest level of expenditure per inhabitant. The Romanian health system is organized on three levels of assistance: primary, secondary and tertiary assistance. This overview presents the organization and the characteristics of pediatric and neonatal healthcare in Romania at all levels, the infrastructure and the human resources, the educational system from medical school to pediatric residency, professional organizations, national health programs, and the child health status in Romania. Infant mortality, the most descriptive single indicator of the quality of a health system, decreased constantly for the last 30 years in Romania, but is still the highest in the European Union. Even though there were great improvements in the healthcare for children, more efforts should be made to assure a better quality of care for the future of our nation, both on the human resources (in great danger due to the brain-drain of medical professionals during the last 12 years), and on the infrastructure plan.

Esophageal atresia with distal fistula - unusual case series. Considerations related to epidemiological aspects, malformative associations, and prenatal diagnosis.

BACKGROUND: Esophageal atresia (EA) is the most frequent and severe congenital anomaly of the esophagus, occurring in 1:2500-1:4500 live births. Five types of EA have been described, EA with tracheoesophageal fistula (TEF) being the most frequent. AIM: The aim of this paper is to evaluate epidemiological aspects, malformative associations, and prenatal diagnosis in an unusual case series of EA with distal TEF. CASE PRESENTATIONS: The authors are analyzing a series of seven cases of EA with distal TEF. The seven cases of EA with TEF presented occurred during a period of two years, resulting in an unusually increased rate - 1.1:1000 live births. Except a late suspicion of EA (one day before delivery), EA was not diagnosed during prenatal scans despite association with polyhydramnios in two cases and single umbilical artery in four cases. None of the two cases of unilateral renal agenesis or anorectal malformations were diagnosed on prenatal ultrasound scans. In two of the cases, EA was part of VACTERL (vertebral defects, anorectal malformations, heart defects, EA with or without TEF, renal anomalies/dysplasia, and limb defects) association. Despite lack of prenatal diagnosis, postnatal diagnosis of EA was suspected at birth in four cases, at two hours in one case. CONCLUSIONS: An increased index of suspicion for congenital structural defects, particularly for EA, should be maintained in the presence of a single umbilical artery and÷or polyhydramnios on prenatal ultrasound scan. Prenatal diagnosis of EA offers the chance for parental counseling, planned birth and transfer for corrective surgery and decreases the risk for postnatal aspiration pneumonia associated with early feedings.

Trends in outcomes of very preterm infants in Romania: A tale of three cities.

BACKGROUND: Although survival of preterm infants has improved, prematurity remains the second most frequent cause of death before 5 years of age in Romania. Data on the changing mortality of Romanian preterm infants born before 29 weeks of gestation have not been available. METHODS: Outcomes of infants of gestational age 25-28 weeks born in 2007-2010 (n = 247) were compared with those born in 2011-2014 (n = 235). Data were analyzed from three tertiary neonatal intensive care centers. Mortality rates and major morbidities were compared between these two epochs. RESULTS: Infants in the later epoch were more likely to have been born by cesarean section and had higher 1 and 5 min Apgar scores. Mortality rate decreased significantly with increasing gestational age at birth. Between the two epochs, the in-hospital mortality rate decreased from 65.6% to 29.4% (P < 0.001); death in the first 48 h decreased from 30.0% to 8.5% (P < 0.001); and prevalence of severe intraventricular hemorrhage decreased from 52.2% to 11.9% (P < 0.001). There were significant increases in the rates of necrotizing enterocolitis and bronchopulmonary dysplasia among survivors but no change in the rate of retinopathy of prematurity. The rate of antenatal corticosteroid use did not change and was only 47% in the more recent epoch (2011-2014). CONCLUSIONS: Overall mortality is decreasing, and infants admitted in the later epoch had substantially different rates of mortality and several serious morbidities. The low rate of antenatal corticosteroid use provides an opportunity for further reductions in mortality and morbidity among very preterm infants born in Romania.

Intubation-Surfactant: Extubation on Continuous Positive Pressure Ventilation. Who are the Best Candidates?

INTRODUCTION: Respiratory distress syndrome (RDS) continues to be the leading cause of illness and death in preterm infants. Studies indicate that INSURE strategy (INtubate-SURfactant administration and Extubate to nasal continuous positive airway pressure [nCPAP]) is better than mechanical ventilation (MV) with rescue surfactant, for the management of respiratory distress syndrome (RDS) in very low birth weight (VLBW) neonates, as it has a synergistic effect on alveolar stability. AIM OF THE STUDY: To identify the factors associated with INSURE strategy failure in preterm infants with gestational age (GA) ≤ 32 weeks. MATERIALS AND METHODS: This was a retrospective cohort study, based on data collected in the Romanian National Registry for RDS patients by three regional (level III) centers between 01.01.2010 and 31.12.2011. All preterm infants of ≤ 32 weeks GA were included. Prenatal and neonatal information were compared between (Group 1), the preterm infants successfully treated using INtubation-SURfactant-Extubation on nasal CPAP (INSURE) strategy and (Group 2 ), those who needed mechanical ventilation within seventy two hours after INSURE. RESULTS: A total of 637 preterm infants with GA ≤ 32 weeks were included in the study. INSURE strategy was performed in fifty seven cases (8.9%) [ Group 1] and was successful in thirty one patients (54.4%). No differences were found as regards the studied prenatal and intranatal characteristics between (Group 1) and Group 2 who needed mechanical ventilation. Group 2 preterm infants who needed mechanical ventilation within 72 hours after INSURE had significantly lower mean Apgar scores at 1 and 5 minutes and lower peripheral oxygen saturation (SpO2) during resuscitation at birth (p<0.05). Successful INSURE strategy was associated with greater GA, birth weight (BW), fraction of inspired oxygen (FiO2) during resuscitation, and an increased mean dose of surfactant but these associations were not statistically significant (p>0.5). CONCLUSION: In preterm infants ≤ 32 weeks gestation, increased INSURE failure rates are associated with complicated pregnancies, significantly lower Apgar scores at 1 and 5 minutes, and lower peripheral oxygen saturation during resuscitation.

Persistent Ductus Arteriosus in Critically Ill Preterm Infants.

INTRODUCTION: Persistent ductus arteriosus (PDA) is found with increased incidence in preterm infants, significantly affecting neonatal morbidity and mortality rates. AIM: To evaluate the association between the presence of PDA and the severity of clinical condition at birth in critically ill preterm infants, with gestational ages (GA) ≤ 32 weeks and severe respiratory distress. METHODS: All preterm infants with GA ≤ 32 weeks admitted to the neonatal intensive care unit (NICU) of the Clinical County Emergency Hospital, Sibiu between 1 January 2010 and 31 December 2015 were included in the study. These were categorized as Group 1 [Preterm infants with PDA; n=154] and Group 2 [Preterm infants without PDA; n=186]. Epidemiological and clinical data were collected in the National Registry for Respiratory Distress Syndrome for all children, and data related to prenatal period, clinical characteristics at birth i.e GA, weight, gender, Apgar scores, and clinical features such as resuscitation at birth, surfactant administration, need and duration of respiratory support, neonatal sepsis, complications associated with prematurity, and death, were analyzed. RESULTS: Group 1 infants had significantly lower GA and birth weights, were more often out born (p=0.049, HR 1.69), and had significantly lower Apgar scores at 1 and 10 minutes (p=0.022, p=0.000). They presented a significantly higher need for surfactant administration (42.9% vs 24.7%, p<0.0001) and respiratory support (96.8% vs 90.3%, HR 3.19, p=0.019 for need of CPAP and 22.1% vs 10.8%, HR 2.35, p=0.004 for mechanical ventilation). Duration of respiratory support was also significantly higher in the Group 1 (7.6%±7.5 vs. 5.1±3.8 days, p<0.0001 for CPAP and 20.1±22.5 vs. 12.0±15.7 days, p<0.0001 for mechanical ventilation). CONCLUSION: In very preterm infants, PDA may be associated with a critical clinical condition leading to serious complications. The presence of PDA after the seventh day of life was associated with an increased need for respiratory support, both CPAP and mechanical ventilation, increased severity of the respiratory distress syndrome, requiring a longer duration of respiratory support, and increased the hospitalization length. In very preterm infants, PDA presence was also associated with a higher rate of severe complications and death, indicating the need for a careful and proper management of these critical cases in neonatal intensive care units.

Aspiration pneumonia in an infant with neurological sequelae - case report.

Aspiration pneumonia is a frequent cause of morbidity and mortality in children with neurological deficits. We present the case of a 4-month-old infant from the Foster Care Center, with severe psychomotor retardation, blindness, and associated cardiac malformation, who was admitted to the Pediatrics Clinic of the Emergency County Hospital of Craiova, Romania, presenting aspiration pneumonia and moderate respiratory insufficiency. Under sustained, early instituted treatment, the evolution was towards death. The chest radiography and histopathological examination of the pulmonary tissue confirmed the diagnosis. The neurological impairment was not only a favoring factor for aspiration, through the deglutition disorders, but it was also an aggravating one, through the bacterial colonization of the lungs.

Mortality and morbidity of very preterm infants in Romania: how are we doing?

BACKGROUND: Birth before 28 weeks of gestation is associated with high mortality and morbidity. The purpose of this study was to examine characteristics associated with in-hospital mortality and morbidity among extremely low-birthweight neonates admitted to three tertiary care centers in Romania. METHODS: The study was conducted in three Romanian hospitals with level-III neonatal intensive care units. We studied singleton live births at the established Romanian limit of viability (i.e., 25-28 weeks' gestational age) born between January 2007 and December 2010 (n = 227). Infants born in non-level-III facilities transferred to these three centers were included in our study (n = 39). Descriptive and multivariate statistical analyses were used to describe the population and examine outcomes and risk factors. RESULTS: During the study period, 62 neonates (27.3%) were delivered at 25 weeks, 56 (24.7%) were delivered at 26 weeks, 56 (24.7%) at 27 weeks, and 53 (23.3%) at 28 weeks. Overall in-hospital mortality was 65% (from 85% at 25 weeks to 35% at 28 weeks). The rates for major morbidities were necrotizing enterocolitis 8.8%, bronchopulmonary dysplasia 12.5%, and retinopathy of prematurity (stage higher than 2) 26.2%. CONCLUSIONS: During 2007-2010, in-hospital survival of infants admitted to three neonatal intensive care units in Romania was 35% and ranged from 14% at 25 weeks to 64% at 28 weeks.