Treatment of retinopathy of prematurity: a review of conventional and promising new therapeutic options

Retinopathy of prematurity (ROP), a retinal vascular disease of premature infants, continues to be a major cause of preventable childhood blindness all over the world. The incidence of ROP varies among countries, being influenced by the quality of the level of neonatal intensive care. Here, we discuss the potential treatments that are now available or will soon or probably be available for ROP. Although ablation of the avascular retina with laser photocoagulation remains the current gold standard and well established therapy for ROP, some new therapeutic options including angiostatic therapies are being explored based on our knowledge of the pathophysiology of the ROP and complications and efficacy of laser treatment. However, prevention of the development of severe ROP and screening for ROP seem to be the best strategy in avoiding visual impairment caused by ROP in premature infants. New therapeutic interventions including vascular endothelial growth factor antibody administration, gene therapy and supplemental therapies should be supported with evidence-based data for the treatment of ROP.

Rh-incompatible hemolytic disease of the newborn in Hefei

BACKGROUND Anti-D antibody is not the common cause of Rh-isoimmunization in Chinese neonatal jaundice.Recent change in national population policy has followed by an increase in Rh-isoimmunization related hemolytic disease of the newborn(HDN).Unfortunately,regional status of Rh-HDN is unavailable.We hypothesize that Rh-HDN in our region is most commonly due to anti-E antibody.AIM To investigate the prevalence of hemolytic disease of the newborn due to Rhisoimmunization in Hefei City.METHODS Retrospective review of data obtained from Children’s Hospital of Anhui and Hefei Blood Center between January 2017 and June 2019.Status of minor blood group antibody was studied in the corresponding mothers.RESULTS Totally 4138 newborns with HDN admitted during the study period and 116(2.8%)received blood exchange transfusion(BET).Eighteen newborns(0.43%)with proven Rh-incompatible HDN were identified.All were not the first-born baby.Thirteen mothers were RhD(+)(72%)and five were RhD(-).The distribution of Rh-related antibodies in mothers was ten anti-E(55%),five anti-D(27%),and for one anti-C,anti-c,and anti-E/c(6%)each.Thirteen(72.2%)were qualified for BET,relative risk for BET was 28.9 as compared to other types of HDN,but only 10 received due to parenteral refusal.All(100%)RhD related HDN received BET which is not significantly different from RhE related HDN(81.8%).CONCLUSION As expected,all Rh-incompatible HDN newborns were not the first-born.Contrary to the Caucasian population,anti-D induced HDN is not the most common etiology.In our region,anti-E(11/18,61%)is the most common cause of Rh-HDN.

What neonatal complications should the pediatrician be aware of in case of maternal gestational diabetes?

In the epidemiologic context of maternal obesity and type 2 diabetes(T2D),the incidence of gestational diabetes has significantly increased in the last decades.Infants of diabetic mothers are prone to various neonatal adverse outcomes,including metabolic and hematologic disorders,respiratory distress,cardiac disorders and neurologic impairment due to perinatal asphyxia and birth traumas,among others.Macrosomia is the most constant consequence of diabetes and its severity is mainly influenced by maternal blood glucose level.Neonatal hypoglycemia is the main metabolic disorder that should be prevented as soon as possible after birth.The severity of macrosomia and the maternal health condition have a strong impact on the frequency and the severity of adverse neonatal outcomes.Pregestational T2 D and maternal obesity significantly increase the risk of perinatal death and birth defects.The high incidence of maternal hyperglycemia in developing countries,associated with the scarcity of maternal and neonatal care,seriously increase the burden of neonatal complications in these countries.

Burden of respiratory syncytial virus infection in young children

Respiratory syncytial virus(RSV) is the most frequent and important cause of lower respiratory tract infection in infants and children. It is a seasonal virus, with peak rates of infection occurring annually in the cold season in temperate climates, and in the rainy season, as temperatures fall, in tropical climates. High risk groups for severe RSV disease include infants below six mo of age, premature infants with or without chronic lung disease, infants with hemodynamically significant congenital heart disease, infants with immunodeficiency or cystic fibrosis, and infants with neuromuscular diseases. Mortality rates associated with RSV infection are generally low in previous healthy infants(below 1%), but increase significantly in children with underlying chronic conditions and comorbidities. Following early RSV lower respiratory tract infection, some patients experience recurrent episodes of wheezing mimicking early childhood asthma with persistence of lung function abnormalities until adolescence. There is currently no RSV vaccine available, but promising candidate vaccines are in development. Palivizumab, a monoclonal RSV antibody that is the only tool for immunoprophylaxis in high-riskinfants, lowers the burden of RSV infection in certain carefully selected patient groups.

Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation:Mechanisms and implications for psychopathology

Accumulating translational evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid(DHA) plays a role in the maturation and stability of cortical circuits that are impaired in different recurrent psychiatric disorders. Specifically, rodent and cell culture studies find that DHA preferentially accumulates in synaptic and growth cone membranes and promotes neurite outgrowth, dendritic spine stability, and synaptogenesis. Additional evidence suggests that DHA may play a role in microglia-mediated synaptic pruning, as well as myelin development and resilience. In nonhuman primates n-3 fatty acid insufficiency during perinatal development leads to widespread deficits in functional connectivity in adult frontal cortical networks compared to primates raised on DHA-fortified diet. Preterm delivery in non-human primates and humans is associated with early deficits in cortical DHA accrual. Human preterm birth is associated with longstanding deficits in myelin integrity and cortical circuit connectivity and increased risk for attention deficit/hyperactivity disorder(ADHD), mood, and psychotic disorders. In general, ADHD and mood and psychotic disorders initially emerge during rapid periods of cortical circuit maturation and are characterized by DHA deficits, myelin pathology, and impaired cortical circuit connectivity. Together these associations suggest that early and uncorrected deficits in fetal brain DHA accrual may represent a modifiable risk factor for cortical circuit maturation deficits in psychiatric disorders, and could therefore have significant implications for informing early intervention and prevention strategies.

Preventing medication errors in neonatology: Is it a dream?

Since 1999, the problem of patient safety has drawn particular attention, becoming a priority in health care. A "medication error"(ME) is any preventable event occurring at any phase of the pharmacotherapy process(ordering, transcribing, dispensing, administering, and monitoring) that leads to, or can lead to, harm to the patient. Hence, MEs can involve every professional of the clinical team. MEs range from those with severe consequences to those with little or no impact on the patient. Although a high ME rate has been found in neonatal wards, newborn safety issues have not been adequately studied until now. Healthcare professionals working in neonatal wards are particularly susceptible to committing MEs due to the peculiarities of newborn patients and of the neonatal intensive care unit(NICU) environment. Current neonatal prevention strategies for MEs have been borrowed from adult wards, but many factors such as high costs and organizational barriers have hindered their diffusion. In general, two types of strategies have been proposed: the first strategy consists of identifying human factors that result in errors and redesigning the work in the NICU in order to minimize them; the second one suggests to design and implement effective systems for preventing errors or intercepting them before reaching the patient. In the future, prevention strategies for MEs need to be improved and tailored to the special neonatal population and the NICU environment and, at the same time, every effort will have to be made to support their clinical application.

Oral medications regarding their safety and efficacy in the management of patent ductus arteriosus

Patent ductus arteriosus(PDA) is a common clinical condition in preterm infants which is inversely related to birth weight and gestational age. Cyclooxygenase inhibitors such as indomethacin and ibuprofen which block the prostaglandin conversion from arachidonic acid are the most commonly used drugs for ductal closure. This review focuses on the safety and efficacy oral medications in the management of PDA in preterm infants. Ibuprofen seems to be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects when compared to indomethacin. PDA closure rates are better with oral than with intravenous ibuprofen probably due to the pharmacokinetic of the drug. However, these medications were reported to be associated with several adverse including transient renal failure, gastrointestinal bleeding and perforation, hyperbilirubinemia and platelet dysfunction. Paracetamol seems be an alternative to PDA therapy with lower adverse events and side effects.

Expression of Clock genes in the pineal glands of newborn rats with hypoxic-ischemic encephalopathy

Clock genes are involved in circadian rhythm regulation, and surviving newborns with hypoxic-ischemic encephalopathy may present with sleep-wake cycle reversal. This study aimed to determine the expression of the clock genes Clock and Bmall, in the pineal gland of rats with hypoxic-ischemic brain damage. Results showed that levels of Clock mRNA v^re not significantly changed within 48 hours after cerebral hypoxia and ischemia. Expression levels of CLOCK and BMAL1 protein were significantly higher after 48 hours. The levels of Bmall mRNA reached a peak at 36 hours, but were significantly reduced at 48 hours. Experimental findings indicate that Clock and Bmall genes were indeed expressed in the pineal glands of neonatal rats. At the initial stage （within 36 hours） of hypoxic-ischemic brain damage, only slight changes in the expression levels of these two genes were detected, followed by significant changes at 36-48 hours. These changes may be associated with circadian rhythm disorder induced by hypoxic-ischemic brain damage.

Neurological consequences of systemic inflammation in the premature neonate

Despite substantial progress in neonatal care over the past two decades leading to improved survival of extremely premature infants, extreme prematurity continues to be associated with long term neurodevelopmental impairments. Cerebral white matter injury is the predominant form of insult in preterm brain leading to adverse neurological consequences. Such brain injury pattern and unfavorable neurologic sequelae is commonly encountered in premature infants exposed to systemic inflammatory states such as clinical or culture proven sepsis with or without evidence of meningitis, prolonged mechanical ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis and chorioamnionitis. Underlying mechanisms may include cytokine mediated processes without direct entry of pathogens into the brain, developmental differences in immune response and complex neurovascular barrier system that play a critical role in regulating the cerebral response to various systemic inflammatory insults in premature infants. Understanding of these pathologic mechanisms and clinical correlates of such injury based on serum biomarkers or brain imaging findings on magnetic resonance imaging will pave way for future research and translational therapeutic opportunities for the developing brain.

Pulmonary immune cells and inflammatory cytokine dysregulation are associated with mortality of IL-1R1^(-/-) mice infected with influenza virus(H1N1)

Respirovirus infection can cause viral pneumonia and acute lung injury （ALl）. The interleukin-1 （IL-1） family consists of proinflammatory cytokines that play essential roles in regulating immune and inflammatory responses in vivo. IL-1 signaling is associated with protection against respiratory influenza virus infection by mediation of the pulmonary anti-viral immune response and inflammation. We analyzed the infiltration lung immune leukocytes and cytokines that contribute to inflammatory lung pathology and mortality of fatal H1N1 virus-infected IL-1 receptor 1 （IL-1R1） deficient mice. Results showed that early innate immune cells and cytokine/chemokine dysregulation were observed with significantly decreased neutrophil infiltration and IL-6, TNF-α, G-CSF, KC, and MIP-2 cytokine levels in the bronchoalveolar lavage fluid of infected IL-1R1^-/- mice in comparison with that of wild type infected mice. The adaptive immune response against the H1N1 virus in IL-1 R1^-/- mice was impaired with downregulated anti-viral Thl cell, CD8＋ cell, and antibody functions, which contributes to attenuated viral clearance. Histological analysis revealed reduced lung inflammation during early infection but severe lung pathology in late infection in IL-1R1^-/- mice compared with that in WT infected mice. Moreover, the infected IL-1R1^--/ mice showed markedly reduced neutrophil generation in bone marrow and neutrophil recruitment to the inflamed lung. Together, these results suggest that IL-1 signaling is associated with pulmonary anti-influenza immune response and inflammatory lung injury, particularly via the influence on neutrophil mobilization and inflammatory cytokine/chemokine production.

Nurses’experiences of caring for preterm infants in pain:A metaethnography

Objective:Preterm infants are subjected to numerous painful procedures during their neonatal intensive care unit(NICU)hospitalization.Despite advancements in pain alleviation,nurses remain challenged to provide timely and effective pain management for preterm infants.Greater understanding of the lived experience of nurses caring for preterm infants in pain could provide novel insights to improve pain management for this vulnerable population.The aim of this meta-ethnography was to synthesize and interpret qualitative findings of nurses’experiences of taking care of preterm infants in pain.Methods:An extensive literature search in PubMed,CINAHL,PsycINFO,Scopus,BIOSIS and ProQuest Dissertation and Theses Database was conducted,including studies within the past 10 years.Two nursing researchers conducted data extraction and analysis independently.Inclusion criteria were applied to search for qualitative studies of nurse participants who worked in the NICU taking care of preterm infants.Studies published in a language other than English,articles that did not include qualitative data and qualitative data that could not be extracted from the findings or did not discuss nurses’experiences were excluded.Critical Appraisal Skills Programme was used for literature quality evaluation.Results:Eight studies remained after further screening according to inclusion and exclusion criteria.These eight studies were conducted from 2013 to 2018 and totally enrolled 205 nurses from Iran,Canada,the United States,Finland,Sweden,Switzerland,and Australia.Five themes emerged on the nurses’perspectives of taking care of preterm infants in pain:1)They sense the neonatal pain;2)Adverse consequences of unrelieved pain;3)Barriers of managing pain;4)Concerns of available approaches for pain relief;5)Failure to work with parents.Conclusions:This meta-ethnography identified nurses’understanding of pain in preterm infants that can be assessed,and they acknowledged that unrelieved pain could cause developmental deficits in infants.The barriers are lack of training and support on pain assessment and intervention in preterm infants.Optimizing workload and environment,developing age-specified pain assessment and intervention,receiving emotional support and training,and building up a rapport with parents are urgent needs for nurses to provide better care to infants having pain.

New Frontiers of Necrotizing Enterocolitis: From Pathophysiology to Treatment

Necrotizing enterocolitis [NEC] is an inflammatory disease of intestine largely occuring in preterm infants with a wide range of damage from minimal injury limited to mucosa to extensive necrosis of bowel wall and perforation. Despite advancements in neonatal care, mortality remains high [30% - 50%] and controversy still persists with regards to the most appropriate management of neonates with necrotizing enterocolitis. The main factors thought to be involved in the pathogenesis of NEC are: relatively hyper-reactive state of premature intestine, enteral feeding and bacterial colonization. In this review, we discuss current knowledge about the epidemiology, pathophysiology, imaging, medical and surgical management of necrotizing enterocolitis and describe novel strategies for prevention and treatment.

Familial hemophagocytic lymphohistiocytosis type 2 in a female Chinese neonate:A case report and review of the literature

BACKGROUND Familial hemophagocytic lymphohistiocytosis type 2(FHL2)is a rare genetic disorder presenting with fever,hepatosplenomegaly,and pancytopenia secondary to perforin-1(PRF1)mutation.FLH2 has been described in Chinese but usually presents after 1 year old.We describe a female Chinese neonate with FHL2 secondary to compound heterozygous PRF1 mutation with symptom onset before 1 mo old.We review Chinese FHL2 patients in the literature for comparison.CASE SUMMARY A 15-d-old female neonate was referred to our hospital for persistent fever and thrombocytopenia with diffuse petechiae.She was born to a G5P3 mother at 39 wk and 4 d via cesarean section secondary to breech presentation.No resuscitation was required at birth.She was described to be very sleepy with poor appetite since birth.She developed a fever up to 39.5°C at 7 d of life.Leukocytosis,anemia,and thrombocytopenia were detected at a local medical facility CONCLUSION A literature review identified 75 Chinese FHL2 patients,with only five presenting in the first year of life.Missense and frameshift mutations are the most common PRF1 mutations in Chinese,with 24.8%having c.1349C>T followed by 11.6%having c.65delC.The c.658G>C mutation has only been reported once in the literature and our case suggests it can be pathogenic,at least in the presence of another pathogenic mutation such as c.1066C>T.

A predictive score for retinopathy of prematurity by using clinical risk factors and serum insulin-like growth factor-1 levels

AIM：To detect the impact of insulin-like growth factor-1（IGF-1）and other risk factors for the early prediction of retinopathy of prematurity（ROP）and to establish a scoring system for ROP prediction by using clinical criteria and serum IGF-1 levels.METHODS：The study was conducted with 127 preterm infants.IGF-1 levels in the 1st day of life,1st,2nd,3rd and4th week of life was analyzed.The score was established after logistic regression analysis,considering the impact of each variable on the occurrences of any stage ROP.A validation cohort containing 107 preterm infants was included in the study and the predictive ability of ROP score was calculated.RESULTS：Birth weights（BW）,gestational weeks（GW）and the prevalence of breast milk consumption were lower,respiratory distress syndrome（RDS）,bronchopulmonarydysplasia（BPD）and necrotizing enterocolitis（NEC）were more frequent,the duration of mechanical ventilation and oxygen supplementation was longer in patients with ROP（P〈0.05）.Initial serum IGF-1 levels tended to be lower in newborns who developed ROP.Logistic regression analysis revealed that low BW（〈1250 g）,presence of intraventricular hemorrhage（IVH）and formula feeding increased the risk of ROP.Afterwards,the scoring system was validated on 107 infants.The negative predictive values of a score less than 4 were 84.3%,74.7%and 79.8%while positive predictive values were 76.3%,65.5%and71.6%respectively.CONCLUSION：In addition to BW〈1250 g and IVH,formula consumption was detected as a risk factor for the development of ROP.Breastfeeding is important for prevention of ROP in preterm infants.

Outcomes of surrogate pregnancies in California and hospital economics of surrogate maternity and newborn care

AIM:To describe maternity and newborn charges for an economic analysis of surrogate pregnancies on the health care resource utilization.METHODS:A retrospective chart review of all women identified as being surrogates and the infants born from these pregnancies was performed between January 1,2012 and December 31,2013.Selected maternity diagnoses,mode of delivery,duration of hospitalization,and hospital charges were collected together with infants' birth weights,gestational age,length of hospital stay,and hospital charges.Charges associated with the in vitro fertilization cycles,artificial insemination,or embryo(s)transfer into the surrogate were not considered in the maternity charges.A ratio contrasting the maternity hospital charges for the surrogate carrier was compared as a ratio to the mean charges for 2540 infants delivered in 2013 after naturalconception and adjusted to the baseline hospital charges for both maternity and newborn care.RESULTS:Analysis of sixty-nine infants delivered from both gestational and traditional surrogate women found an increased in multiple births,NICU admission,and length of stay with hospital charges several multiples beyond that of a term infant conceived naturally and provided care in our nursery.Among singletons and twins(per infant)hospital charges were increased 26 times(P < 0.001)and in triplets charges were increased 173 times(P < 0.0001)when compared to a term infant provided care in a normal nursery at our center.CONCLUSION:Maternity costs for surrogates exceed those of women who conceive naturally,and these costs are especially magnified in women with triplets and multiple births.

Quantitative optical measurement of mitochondrial superoxide dynamics in pulmonary artery endothelial cells

Reactive oxygen species(ROS)play a vital role in cell signaling and redox regulation,but when present in excess,lead to numerous pathologies.Detailed quantitative characterization of mitochondrial superoxide anion(O^(·-)_(2))production in fetal pulmonary artery endothelia cells(PAECs)has never been reported.The aim of this study is to assess mitochondrial O^(·-)_(2)pro-duction in cultured PAECs over time using a novel quantitative optical approach.The rate,the sources,and the dynamics of O^(·-)_(2)production were assessed using targeted metabolic modulators of the mitochondrial electron transport chain(ETC)complexes,specifically an uncoupler and inhibitors of the various ETC complexes,and inhibitors of extra-mitochondrial sources of O^(·-)_(2).After stabilization,the cells were loaded with nanomolar mitochondrial-targeted hydroethidine(Mito-HE,MitoSOX)online during the experiment without washout of the residual dye.Time-lapse fuorescence microscopy was used to monitor the dynamic changes in O^(·-)_(2)fluorescence intensity over time in PAECs.The transient behaviors of the fuorescence time course showed exponential increases in the rate of O^(·-)_(2) production in the presence of the ETC uncoupler or inhibitors.The most dramatic and the fastest increase in O^(·-)_(2)production was observed when the cells were treated with the uncoupling agent,PCP.We also showed that only the complex IV inhibitor,KCN,attenuated the marked surge in O^(·-)_(2)production induced by PCP.The results showed that mitochondrial respiratory complexes I,III and IV are sources of O^(·-)_(2) production in PAECs,and a new observation that ROS production during uncoupling of mitochondrial res-piration is mediated in part via complex IV.This novel method can be applied in other studies that examine ROS production under stress condition and during ROS mediated injuries in vritro.

Gastrointestinal symptoms as the first sign of chronic granulomatous disease in a neonate: A case report

BACKGROUND Chronic granulomatous disease(CGD)characterized by recurrent and severe bacterial and fungal infections is most common in childhood.CASE SUMMARY We reported a 24-d-old male infant who developed gastrointestinal symptoms as the first sign of CGD.CONCLUSION Gastrointestinal symptoms representing the first sign of CGD are very rare,and prompt diagnosis and treatment with broad-spectrum antibiotics were of crucial importance.

Multiple Infantile Myofibromatosis with Skeletal Abnormalities

Background: Infantile myofibromatosis is an uncommon disorder characterized by multiple fibromatous tumours involving skin, bone, muscle, viscera and subcutaneous tissue. It is a rare benign mesenchymal tumour;most commonly occurs in infancy or early childhood. The clinical presentation can mimic malignant tumours of infancy or childhood. Case Presentation: We describe a rare case of multicentric Infantile myofibromatosis in a 6-month-old infant presenting with multiple scalp swellings and associated skeletal abnormalities (adducted thumbs, clinodactyly and bilateral hallux valgus deformity of great toes). The case required surgical excision of all scalp lesions and orthopedic manipulation of skeletal abnormalities. Conclusion: Infantile myofibromatosis presenting as multiple lesions in the scalp associated with skeletal abnormalities, is very rare. To best of our knowledge, the unique combination of the distinct skeletal abnormalities in infantile myofibromatosis has not been reported so far. This report emphasizes the possibility of skeletal abnormalities in infantile myofibromatosis.

Effects of Late Preterm Birth on the Incidence of Developmental Delays among Children at 3 Years of Age: A Matched-Pair Case-Control Study

Purpose: To investigate the relationship between preterm delivery and developmental outcomes in children born at 34 - 36 weeks of gestation (late preterm period). Methods: This study reviewed the cases of singleton late preterm children and full-term (38 - 40 weeks of gestation) children born at Showa University Hospital. The developmental outcomes at 3 years of age were assessed based on the results of questionnaires sent to the families by mail. In addition, the incidence of developmental delays was compared between the late preterm and full-term children. In the full-term control group, perinatal characteristics (neonatal gender, Apgar score, Cesarean delivery, birth weight < 10th percentile, birth weight < 3rd percentile) were matched with those of the late preterm cases. We compared categorical variables using Fisher’s exact test. For variables with a non-normal distribution, Welch’s t-test was applied. A p-value of <0.05 was considered to be statistically significant. Results: The rate of return of the questionnaires was 25.9% (121) among the cases and 25.8% (163) among the controls. The frequency of developmental delays was 6.6% among the cases, compared with 4.3% among the controls. Conclusions: Matching the perinatal characteristics of the subjects, the frequency of developmental delays was similar between the two groups.

Satisfying Toilet Needs in Pre-School —Experiences of 5 - 6 Years Old

Background: It is known that, for reasons of hygiene and/or anxiety, some first year primary school children actively choose to avoid going to the toilet whilst at school, while at the same time many young children’s primary care visits are due to urinary tract and bowel problems. By this age most children can recognise the bodily signals indicating the need for a toilet visit, and can independently perform the associated routines. Aim of this study was to describe the experience of healthy 5 to 6 years old when needing and using toilets whilst at pre-school. Methods: A qualitative descriptive method was used. Seventeen children aged 5 to 6 years were interviewed. Results: Nearly all used the toilet when the need arose, but there were times during the day when their freedom to use the toilet was restricted. Most children experienced periods of waiting outside the toilet and a long wait could result in a decision to not use it. On those occasions when help was needed, it was usually necessary to shout once or more in order to attract the teacher’s attention. Some children found the toilets clean and fresh while others found them dirty and smelly. Privacy during toilet visits was desirable among the children but queue outside the toilet was a cause of worry. Conclusion: The children were mostly able to use the toilet whilst at preschool, despite the challenges to their senses and integrity and occasionally issues with the teacher’s rules. The need for privacy often had to yield to the teacher’s need to control the children or even because toilet doors and/or locks were not adapted to the children’s requirements.