Preventing bronchopulmonary dysplasia: new tools for an old challenge.

Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease in infants and presents as a consequence of preterm birth. Due to the lack of effective preventive and treatment strategies, BPD currently represents a major therapeutic challenge that requires continued research efforts at the basic, translational, and clinical levels. However, not all very low birth weight premature babies develop BPD, which suggests that in addition to known gestational age and intrauterine and extrauterine risk factors, other unknown factors must be involved in this disease's development. One of the main goals in BPD research is the early prediction of very low birth weight infants who are at risk of developing BPD in order to initiate the adequate preventive strategies. Other benefits of determining the risk of BPD include providing prognostic information and stratifying infants for clinical trial enrollment. In this article, we describe new opportunities to address BPD's complex pathophysiology by identifying prognostic biomarkers and develop novel, complex in vitro human lung models in order to develop effective therapies. These therapies for protecting the immature lung from injury can be developed by taking advantage of recent scientific progress in -omics, 3D organoids, and regenerative medicine.

The use of two or more courses of low-dose systemic dexamethasone to extubate ventilator-dependent preterm neonates may be associated with a higher prevalence of cerebral palsy at two years of corrected age.

BACKGROUND: Our objective was to determine whether the use of two or more courses of low-dose systemic dexamethasone for extubation of ventilator-dependent preterm infants after the first week of life, as proposed in the DART study, is associated with greater neurodevelopmental harm at two years of corrected age, compared to a single course. METHODS: Retrospective review at seven level III neonatal intensive care units. Preterm infants who underwent only one course of systemic dexamethasone for extubation were grouped into DART-1; those who underwent two or more courses were grouped into DART-2. Data and outcomes of infants in DART-2 were compared with those in DART-1. RESULTS: 150 preterm infants were studied: 104 in DART-1 and 46 in DART-2. Patients in DART-2 had a lower gestational age (25 vs. 26 weeks, p = 0.031) and greater morbidity. The average dexamethasone cumulative dose for patients in DART-1 was 0.819 mg/kg, vs. 1.697 mg/kg for patients in DART-2. A total of 14 patients died. The neuromotor and neurosensory assessments at two years of corrected age revealed in the DART-2 survivors, after the multivariate analysis, a higher prevalence of cerebral palsy with functional motor class 2 (OR = 6.837; 95%CI: 1.054-44.337; p = 0.044) and ophthalmological problems requiring the use of glasses (OR = 4.157; 95%CI: 1.026-16.837; p = 0.046). CONCLUSIONS: In this cohort, the use of more than one course of systemic dexamethasone in low doses for extubation of ventilator-dependent premature infants after the first week of life was associated, at two years of corrected age, with a higher prevalence of cerebral palsy with functional motor class 2 and ophthalmological problems requiring the use of glasses.

Blueberry Muffin Syndrome and Hyperleukocytosis in a Newborn: A Diagnostic Challenge.

Blueberry muffin syndrome (BMS) in neonates, characterized by widespread nodular lesions, presents diagnostic challenges due to its diverse etiologies. Hyperleukocytosis, with leukocyte counts exceeding 100,000/µL, is a rare phenomenon associated with severe complications in neonates. Congenital leukemia (CL), a rare diagnosis within the first month of life, is linked to high mortality. This case report presents a unique case of BMS with hyperleukocytosis as the initial presentation of CL. A full-term male newborn, born after an uncomplicated pregnancy, except for Kell isoimmunization, with an Apgar score of 9/10, and an irrelevant family history, showed widespread purple nodules consistent with BMS at birth. Laboratory workup revealed mild anemia, hyperleukocytosis with immature granulocytes on peripheral blood (PB) smear, positive direct antiglobulin test, and elevated alanine aminotransferase and lactate dehydrogenase, without hyperbilirubinemia. Empirical antibiotics and hyperhydration were started, and the neonate was transferred to a level 3 neonatal intensive care unit for further evaluation. A comprehensive etiological investigation was conducted, comprising infectious, immunological, metabolic, and neoplastic factors. A skin nodule biopsy revealed an infiltrate of blast cells, indicative of leukemia cutis, and a bone marrow aspirate confirmed acute myeloid leukemia (AML). The patient successfully completed the NOPHO-DBH-2012 chemotherapy protocol at five months and remains in complete remission at nine months. This case report contributes to the literature by highlighting the diagnostic approach and management strategies for CL presenting with BMS and hyperleukocytosis. This case aims to enhance awareness and understanding of BMS as an initial manifestation of CL. Additionally, the challenges of treating leukemia in neonates, coupled with the lack of specific guidelines for this age group, further underscore the complexities in managing such patients.

The role of the human leukocyte antigen system in retinopathy of prematurity: a pilot study.

AIM: To assess the association between the human leukocyte antigen system and retinopathy of prematurity. METHODS: Neonates of <32 weeks of gestational age, born at two level III neonatal intensive care units from January 2000 to December 2001 and from January 2006 to June 2009, were included in the study. Demographic and clinical data were recorded, and retinopathy was classified according to the International Classification. Epithelial cells were collected from the oral cavity and the HLA were studied using the PCR/SSO method. Univariate and multivariate analyses were performed using SPSS® v.18. RESULTS: We evaluated 156 neonates, including 82 (52.6%) males. Median gestational age was 29 (23-31) weeks, and median birth weight was 1030 (525-1935) grams. Seventy (44.9%) of the neonates developed retinopathy. Alleles HLA-B*38, HLA-Cw*12, HLA-DRB1*09, HLA-DRB1*14 (univariate analysis) and HLA-A*68 and HLA-Cw*12 were associated to retinopathy (multivariate analysis). CONCLUSION: The results suggest that the HLA system may be associated with the development of retinopathy of prematurity. A large-scale population-based study should be performed to clarify this association.

Use of Therapeutic Hypothermia in Sudden Unexpected Postnatal Collapse: A Retrospective Study.

INTRODUCTION: Sudden and unexpected postnatal collapse is a rare event with potentially dramatic consequences. Intervention approaches are limited, but hypothermia has been considered after postnatal collapse. The aim of this study was to analyse sudden and unexpected postnatal collapse cases that underwent therapeutic hypothermia in the five Portuguese hypothermia centres. MATERIAL AND METHODS: In this multicentre, retrospective and descriptive study, clinical, ultrasonography, amplitude-integrated electroencephalography and brain magnetic resonance findings of newborns with postnatal collapse that underwent therapeutic hypothermia are reported (2010 - 2018). Statistical analysis was performed by using IBM SPSS Statistics version 21. RESULTS: Twenty-two cases of sudden and unexpected postnatal collapse were referred for therapeutic hypothermia (82% outborn), all ≥ 36 weeks, with Apgar 5´ ≥ 8. Collapse occurred during the first two hours in 73% (all < 24 hours), 50% during skin-to-skin care, 55% related to feeding and 23% during co-bedding. Moderate-severe encephalopathy and severe acidosis were observed (median: Thompson score 16, pH 6.90, base deficit 22 mmol/L). Amplitude-integrated electroencephalogram was abnormal in 95% and magnetic resonance imaging showed severe brain injury in 46%. The mortality rate was 50%. A possible cause was identified in 27%. DISCUSSION: The incidence rate of 2.7 sudden cases of postnatal collapse per 100 000 births, is possibly under-estimated. All infants suffered the collapse in the first day, mostly within the first two hours, as reported before. Possible causes were identified in less than a third of cases, but multiple predisposing conditions were identified, suggesting that prevention may be possible. Newborn positioning and skin-to-skin care have been the most discussed practices. A significant proportion of infants had poor outcomes. Lower Thompson score, electroencephalogram amplitude normalization and normal magnetic resonance imaging seemed to indicate better outcomes. Although conclusive trials on therapeutic hypothermia after postnatal collapse are not available, its use has been considered individually. No severe adverse effects directly related to hypothermia were registered in this study, but the results do not allow drawing meaningful conclusions. CONCLUSION: In our national sample of 22 infants who suffered sudden and unexpected postnatal collapse and underwent therapeutic hypothermia, a significant proportion had poor outcomes. Absolute conclusions from our experience with hypothermia in postnatal collapse cannot be drawn, but systematic reporting of cases and long-term clinical evaluation would facilitate understanding of the real benefits of hypothermia. As this procedure has not been validated with clinical trials for this indication, its use should be considered on a case-by-case approach. The potentially avoidable nature of unexpected postnatal collapse is evident from its association with certain behaviours and risk factors. Surveillance practices during the first hours should be implemented, whilst the benefits of breastfeeding and skin-to-skin care should continue to be widely promoted.

Introdução: O colapso pós-natal súbito inesperado, apesar de raro, condiciona potenciais consequências dramáticas. As intervenções terapêuticas são limitadas, mas a hipotermia induzida tem sido considerada após estes eventos. O objetivo deste estudo foi analisar os casos de colapso pós-natal súbito inesperado submetidos a hipotermia induzida nos cinco centros portugueses que a realizam. Material e Métodos: Estudo descritivo retrospetivo multicêntrico dos recém-nascidos submetidos a hipotermia induzida após colapso pós-natal entre 2010 e 2018. Foram analisadas as variáveis clínicas, a monitorização por eletroencefalograma de amplitude integrada e imagem por ultrassonografia e a ressonância magnética cerebral. A análise estatística foi efetuada com apoio do IBM SPSS Statistics version 21. Resultados: Foram submetidos a hipotermia terapêutica por colapso súbito 22 recém-nascidos, 82% outborn, todos com 36 ou mais semanas de gestação e Apgar 5´ ≥ 8. A situação ocorreu nas primeiras duas horas de vida em 73% (todos com menos de 24 horas de vida), 50% no contacto pele-a-pele, 55% associados à amamentação e 23% durante partilha de cama. Os recém-nascidos observados apresentaram encefalopatia moderada a grave e acidose grave (mediana: Thompson 16, pH 6,90, défice bases 22 mmol/L). Entre os recém-nascidos, 95% registaram alteração no eletroencefalograma e 46% padrões graves de ressonância cerebral. A taxa de mortalidade foi de 50%. Identificaram-se possíveis causas em 27%. Discussão: Estimou-se uma incidência de 2,7 casos de colapso pós-natal súbito inesperado por cada 100 000 nascimentos, um valor possivelmente subestimado. O colapso ocorreu no primeiro dia em todas as crianças, a maioria nas primeiras duas horas, tal como descrito em publicações anteriores. Identificaram-se possíveis causas em menos de um terço dos casos, mas múltiplas condições predisponentes foram referidas, o que sugere a possibilidade de adoção de medidas preventivas. O posicionamento do recém-nascido e o contacto pele-a-pele têm sido as práticas mais discutidas. Uma proporção significativa das crianças teve uma evolução desfavorável. Um desfecho mais positivo parece ter ocorrido nos casos em que se verificaram valores inferiores na escala de Thompson, normalização do eletroencefalograma de amplitude integrada e ressonância magnética normal. Embora não estejam disponíveis ensaios conclusivos sobre a utilização da hipotermia terapêutica após o colapso pós-natal, o seu uso tem sido considerado individualmente. Nesta revisão não foram observados efeitos adversos diretamente relacionados com o procedimento, mas os resultados não permitem obter conclusões significativas. Conclusão: Na nossa amostra nacional de 22 crianças que sofreram colapso súbito pós-natal e submetidas a hipotermia terapêutica, uma proporção significativa teve uma evolução desfavorável. A nossa experiência e a raridade da entidade clínica não permitem delinear conclusões precisas sobre a aplicação da hipotermia induzida no colapso pós-natal súbito inesperado, pelo que se considera essencial a prevenção. O benefício desta terapêutica poderá ser clarificado através do registo sistemático dos casos e do seguimento a longo prazo das crianças. Embora não existam ensaios clínicos que permitam a sua validação após estes eventos, a hipotermia induzida deve ser uma opção a considerar individualmente. A associação do colapso pós-natal com determinados comportamentos e fatores de risco evidenciam a sua potencial prevenção. Devem ser implementadas estratégias de monitorização nas primeiras horas de vida que permitam simultaneamente a contínua promoção da amamentação e do contacto pele-a-pele.

Chorioamnionitis and brain damage in the preterm newborn.

AIM: To evaluate the association between histological chorioamnionitis and brain damage (intraventricular hemorrhage and cystic periventricular leukomalacia) in the preterm newborn. METHODS: This was a retrospective study on neonates born at less than 34 weeks gestational age, and their respective mothers, at three tertiary medical centers in the north of Portugal, from January 2001 to December 2002. RESULTS: The study included 452 newborns (235 male/217 female; birth weight 1440 (515-2620) grams; gestational age 31 (23-33) weeks), 125 from mothers whose placenta showed signs of chorioamnionitis and 327 from mothers without the condition. The association between histological chorioamnionitis and: (1) intraventricular hemorrhage grades I-IV was OR 1.43 (95% CI 0.49-3.94); (2) intraventricular hemorrhage grades III and IV was OR 2.49 (95% CI 1.20-5.11); (3) cystic periventricular leukomalacia was OR 3.02 (95% CI 1.50-6.07). The association, adjusted for birth weight and gestational age, between chorioamnionitis and: (1) intraventricular hemorrhage grades III and IV was OR 0.94 (95% CI 0.39-2.28); (2) cystic periventricular leukomalacia was OR 1.94 (95% CI 1.03-4.61). The association between histological chorioamnionitis with funisitis and/or vasculitis and: (1) intraventricular hemorrhage grades I to IV was OR 1.27 (95% CI 0.52-3.10); (2) cystic periventricular leukomalacia was OR 2.08 (95% CI 0.72-5.98). CONCLUSION: This study confirms the association between histological chorioamnionitis and cystic periventricular leukomalacia, but was unable to confirm the association between histological chorioamnionitis and intraventricular hemorrhage.

[Chorioamnionitis and lung damage in the extremely low birth weight infant]. / Corioamnionite e lesão pulmonar no recém-nascido de extremo baixo peso.

UNLABELLED: Some experimental work suggests that exposure to intrauterine infection is associated, not only, with lung maturation and a reduced risk of respiratory distress syndrome, but also, with delayed alveolarization and increased risk of bronchopulmonary dysplasia. AIM: To evaluate the association between histological chorioamnionitis and lung disease in extremely low birth weight preterm infants. METHODS: A retrospective chart review of 63 less than 1000 g birthweight, appropriated for gestational age neonates, delivered at three tertiary medical centers in the north of Portugal, between 2001 and 2002. The association between histological chorioamnionitis and lung damage (respiratory distress syndrome and bronchopulmonary dysplasia) was evaluated through the calculation of crude and adjusted odds ratio. RESULTS: There were 32 newborns from mothers with histological chorioamnionitis and 31 without the condition. The association between histological chorioamnionitis and respiratory distress syndrome was OR 0.23 (95% CI 0.01 - 2.51). The association between chorioamnionitis and bronchopulmonary dysplasia was OR 1.61 (95% CI 0.38 - 6.97). The association between histological chorioamnionitis and bronchopulmonary dysplasia when adjusted for gestational age, multiple birth and C-section revealed no statistical significance: OR 2.66 (95% CI 0.36 - 19.60) for chorio- amnionitis without funisitis or vasculitis and OR 1.68 (95% CI 0.25 - 11.18) for funisitis and/or vasculitis. CONCLUSION: In this study we could not confirm a decreased risk of respiratory distress syndrome nor an increased risk of bronchopulmonary dysplasia in extremely low birth weight preterm neonates with histological chorioamnionitis

Congenital cystic adenomatoid malformation of the lung--the experience of five medical centres.

BACKGROUND: The clinical spectrum of congenital cystic adenomatoid malformation of the lung (CCAML) ranges from asymptomatic lesions to neonatal respiratory distress and hydrops fetalis. AIM: To review our experience with CCAML, emphasising natural history, management and outcome. MATERIAL AND METHODS: A retrospective chart review of all CCAML-diagnosed neonates admitted to the neonatal intensive care units of five tertiary medical centres in the north of Portugal between 1996 and 2005. RESULTS: Fifteen neonates with CCAML were identified, 9F/6M, birth weight 3100 g (645-3975), gestational age 38 weeks (24-40). The incidence of CCAML was 1: 9300 births. There were 11 (73%) cases of cystic lung lesion diagnosed during pregnancy, median age 22 weeks (19-30). The lesion was right sided in six (40%) and left sided in nine (60%) cases. In utero spontaneous regression of the lesion was observed in two cases. Antenatal intervention (pleurocentesis and thoracoamniotic shunting) was performed in one foetus with impending hydrops. Normal lung radiographic findings at birth were present in five cases, with an abnormal CT scan. Three (20%) neonates became symptomatic during the neonatal period (respiratory distress) and one (70%) after the neonatal period (spontaneous pneumothorax). Two neonates (13%) died. Six (40%) patients underwent thoracotomy and appropriate excisional surgery. Histological examination showed definitive features of CCAML (Stocker classification: type I = 4; type II = 1; type III = 2). Eight (53%) patients remain asymptomatic and did not undergo surgery. CONCLUSIONS: Antenatally diagnosed CCAML has a good prognosis in the absence of severe foetal distress; normal radiographic findings at birth do not rule out CCAML; treatment of asymptomatic CCAML is controversial; surgery may be advocated because of its low morbidity and the prevention of late complications such as malignancy.

Neonatal Hemophilia: A Rare Presentation.

Hemophilia A is a X-linked hereditary condition that lead to decreased factor VIII activity, occurs mainly in males. Decreased factor VIII activity leads to increased risk of bleeding events. During neonatal period, diagnosis is made after post-partum bleeding complication or unexpected bleeding after medical procedures. Subgaleal hemorrhage during neonatal period is a rare, severe extracranial bleeding with high mortality and usually related to traumatic labor or coagulation disorders. Subgaleal hemorrhage complications result from massive bleeding. We present a neonate with unremarkable family history and uneventful pregnancy with a vaginal delivery with no instrumentation, presenting with severe subgaleal bleeding at 52 hours of life. Aggressive support measures were implemented and bleeding managed. The unexpected bleeding lead to a coagulation study and the diagnosis of severe hemophilia A. There were no known sequelae. This case shows a rare hemophilia presentation reflecting the importance of coagulation studies when faced with unexplained severe bleeding.

A Novel Noonan Syndrome RAF1 Mutation: Lethal Course in a Preterm Infant.

Noonan syndrome is a relatively common and heterogeneous genetic disorder, associated with congenital heart defect in about 50% of the cases. If the defect is not severe, life expectancy is normal. We report a case of Noonan syndrome in a preterm infant with hypertrophic cardiomyopathy and lethal outcome associated to acute respiratory distress syndrome caused by Adenovirus pneumonia. A novel mutation in the RAF1 gene was identified: c.782C>G (p.Pro261Arg) in heterozygosity, not described previously in the literature. Consequently, the common clinical course in this mutation and its respective contribution to the early fatal outcome is unknown. No conclusion can be established regarding genotype/phenotype correlation.

Congenital disorders of glycosylation with neonatal presentation.

Congenital disorders of glycosylation (CDG) are a group of hereditary diseases characterised by deficiency of enzymes involved in proteins glycosylation. We describe the clinical case of a neonate with CDG type 1a, nowadays designated phosphomannomutase 2 (PMM2)-CDG. Physical examination showed an abnormal facies, axial hypotonia, abnormal fat distribution, inverted nipples, non-palpable testicles and arachnodactyly. Progressive multiple system organ involvement and worsening of hypertrophic cardiomyopathy occurred. Metabolic study revealed a CDG disturbance, which was confirmed by genetic study. The following mutations were identified: c.193G>T; p.D65Y and c.470T>C; p.F157S. Clinical deterioration was inevitable with multisystemic failure and death. CDG represents a challenge for physicians due to multiple organ involvement, and heterogeneous clinical manifestations. The neonatal form is usually associated with the worst prognosis.

A case of Protracted Diarrhea in a Newborn: a Diagnostic Challenge.

Congenital diarrhea comprises a broad range of pathologies and often requires a thorough workup and immediate treatment. Although rare, microvillous inclusion disease (MVID) should be included in differential diagnosis of this presentation in the neonate. We report the case of a 36-week newborn who developed signs of severe dehydration and lethargy, requiring fluid resuscitation and total parenteral nutrition. MVID was diagnosed by recognition of profuse secretory diarrhea after an exhaustive etiological investigation, confirmed by DNA analysis.

Severe pertussis in newborns and young vulnerable infants.

A retrospective chart review of 18 nonvaccinated newborns and infants admitted to 6 intensive care units in the north of Portugal between 2007 and 2012 revealed a high rate of admissions in 2012 along with significant rates of severe pulmonary hypertension and mortality. Hyperleukocytosis was significantly associated with a more severe clinical picture and mortality.

Cord blood levels of IL-6, IL-8 and IL-10 may be early predictors of bronchopulmonary dysplasia in preterm newborns small for gestational age.

INTRODUCTION: Various cytokines have been associated to the occurrence of bronchopulmonary dysplasia (BPD) in preterm neonates. AIM: To establish an association between cord blood cytokines and BPD, so that they could be used, in clinical practice, as early markers of BPD. MATERIAL AND METHODS: Preterms less than 30 weeks gestational age, were analysed by ELISA microassay for venous cord blood IL-1ß, IL-6, IL-8, TNF-α and IL-10, and compared between the BPD and non-BPD groups. RESULTS: One hundred and fifty neonates completed the study; 31 (21%) small for gestational age (SGA); 16 were deceased before 28 days of life; 36 developed mild BPD and 20 developed moderate/severe BPD. Elevated cord blood IL-8 was associated with death or moderate/severe BPD. SGA patients with moderate/severe BPD presented higher cord blood values of IL-8, lower IL-6 and IL-10 when compared with SGA without moderate/severe BPD; and higher IL-8 levels when compared with patients without moderate/severe BPD. CONCLUSION: These results support an association between cord blood IL-8 and moderate/severe BPD, independently of the intra-uterine growth; and the association of cord blood IL-6 and IL-10 and moderate/severe BPD in SGA preterm newborns.

Value of Chest Radiographic Pattern in RSV Disease of the Newborn: A Multicenter Retrospective Cohort Study.

Respiratory syncytial virus (RSV) lower respiratory tract infection is the most common viral respiratory infection in infants. Several authors have sought to determine which risk factors are the best predictors for severe RSV disease. Our aim was to evaluate if a specific chest radiographic pattern in RSV disease can predict the disease severity. We conducted a multicenter retrospective cohort study in term and preterm neonates with confirmed lower respiratory tract RSV infection, admitted to neonatal intensive care units (NICU) from 2000 to 2010. To determine which factors independently predicted the outcomes, multivariate logistic regression analysis was performed. A total of 259 term and preterm neonates were enrolled. Patients with a consolidation pattern on the chest radiograph at admission (n = 101) had greater need for invasive mechanical ventilation (OR: 2.5; P = .015), respiratory support (OR: 2.3; P = .005), supplemental oxygen (OR: 3.0; P = .008), and prolonged stay in the NICU (>7 days) (OR: 1.8; P = .025). Newborns with a consolidation pattern on admission chest radiograph had a more severe disease course, with greater risk of invasive mechanical ventilation, respiratory support, supplemental oxygen, and prolonged hospitalization.

HLA and bronchopulmonary dysplasia susceptibility: a pilot study.

There is little data on the association between Human Leucocyte Antigen (HLA) alleles and Bronchopulmonary Dysplasia (BPD) of the preterm newborn. Our aim was to assess associations between HLA alleles and BPD susceptibility. We studied 156 preterm neonates (82 M/ 74 F) < 32 weeks gestational age, alive at 36 weeks gestational age. Detailed clinical data were collected. HLA typing was performed by PCR-SSO. HLA allele frequencies where determined by direct counting for BPD and no-BPD groups. Comparison between BPD and no BPD groups was performed using t-test, χ2 test or Fisher exact test and logistic regression as appropriate. Relative risks (RR) and their 95% confidence intervals (95% CI) were also calculated as association measures. We diagnosed 56 (35.9%) neonates with mild BPD and 27 (17%) with moderate/ severe BPD. We found a significant association between HLA-DRB1*01 and mild BPD (OR=3.48[1.23-10.2]).The alleles HLA-A*24, -A*68, -B*51,-Cw*07, -Cw*14, -Cw*15 and -DRB1*01 presented a significant association with moderate/ severe BPD. When adjusted to gestational age and birth weight HLA-A*68 (OR=5.41[1.46; 20.05]), -B*51 (OR=3.09[1.11; 8.63]) and -Cw*14 (OR=4.94[1.15; 21.25]) were significantly associated with moderate/ severe BPD. Conclusion - Our findings suggest an association between HLA-A*68, -B*51 and -C*14 and BPD susceptibility, and that an autoimmune mechanism may be implicated in the pathogenesis of the disease.