Recombinant human erythropoietin (rhEPO) treatment is an alternative to erythrocyte transfusions in neonates with anemia of prematurity (AOP). This study assesses the impact of rhEPO administration within the first week of life on the incidence of AOP (any stage, individual AOP stages, and red-blood-cell (RBC) transfusions. Out of 108 preterm neonates, 49 were administered rhEPO and compared to the remaining group using univariate and multivariate analyses. Univariately, gestational age (GA), birth weight (BW), hemoglobin (Hb), hematocrit (HCT), and RBC levels, and iron administration were significantly associated to AOP (p<0.05 each); however, only the latter remained significant after adjusting for covariates (AOR: 2.75, 95% CI, 1.06–7.11). Multinomial analysis revealed rhEOP therapy was associated with a near 3-fold reduction in moderate AOP incidence (OR: 0.36, 95% CI, 0.15–0.89). Furthermore, ANCOVA revealed positive correlations between rhEPO administration and 21-day Hb (p<0.01), HCT (p<0.05), and EPO (p<0.001) levels. The results confirm previously reported benefits of rhEPO treatment, such as reduced moderate AOP incidence and increased Hb, HCT, and serum EPO levels.

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in neonates as a consequence of preterm birth and arrested fetal lung development. The incidence of BPD remains on the rise, as a result of increasing survival of extremely preterm infants. Severe BPD contributes to significant health care costs and is associated with prolonged hospitalizations, respiratory infections, and neurodevelopmental deficits. In this study, we aimed to detect novel biomarkers of severe BPD. We collected tracheal aspirates (TA) from preterm babies with mild/moderate (n = 8) and severe (n = 17) BPD, and we profiled the expression of 1048 miRNAs using a PCR array. Associations with biological pathways were determined with the Ingenuity Pathway Analysis (IPA) software. We found 31 miRNAs differentially expressed between the two disease groups (2-fold change, FDR < 0.05). Of these, 4 miRNAs displayed significantly higher expression levels, and 27 miRNAs had significantly lower expression levels in the severe BPD vs. the mild/moderate BPD group. IPA identified cell signaling and inflammation pathways associated with miRNA signatures. We conclude that TAs of extreme premature infants contain miRNA signatures associated with severe BPD. These signatures may serve as biomarkers of disease severity in infants with BPD.

Respiratory distress syndrome (RDS) is a major respiratory morbidity associated with prematurity. In this case-control study, we prospectively evaluated whether targeted metabolomic analysis (gas chromatography–mass spectrometry) of the gastric fluid obtained from very preterm neonates (< 32 weeks’ gestation) during the first hour after birth could predict the need for exogenous surfactant for the treatment of RDS. 43 infants with RDS necessitating surfactant (cases) were compared with 30 infants with mild or no RDS (controls) who were not treated with surfactant. Perinatal and neonatal characteristics were recorded. Univariate analysis showed significant differences between the two groups in gastric fluid metabolites (L-glycine and acetyl-L-serine) and clinical parameters (gestational age, 1- and 5-minute Apgar scores, and intubation in the delivery room). Moreover, multivariate analysis revealed intubation in the delivery room as the most potent clinical predictor of surfactant administration [AUC of 0.69 (95% CI 0.57-0.81)]. The combination of metabolomic and clinical data allowed for the construction of a model with good accuracy [AUC 0.76 (95% CI 0.64-0.86)] in predicting surfactant replacement therapy. Further research is required to explore the role of gastric fluid metabolomics in the prediction of RDS and other neonatal outcomes.

Prediction of survival in very preterm infants is very important in terms of clinical medicine and parent counseling. In this prospective study involving 96 very preterm infants, we evaluated whether metabolomic analysis of gastric fluid and urine samples obtained soon after birth could predict survival on days of life (DOL) 3 and 15 as well as overall survival up to hospital discharge. Gas chromatography-mass spectrometry (GC-MS) profiling was used. Uni- and multivariate statistical analyses were carried out to evaluate significant metabolites and their prognostic value. Differences in several metabolites were identified between survivors and non-survivors at the time-points of the study. Binary logistic regression showed that certain metabolites in the gastric fluid including arabitol as well as succinic, erythronic and threonic acids was associated with DOL 15 and overall survival. Gastric glyceric acid was also associated with DOL 15 survival. Urine glyceric acid could predict survival on DOL 3 and overall survival. In conclusion, non-surviving preterm infants showed a different metabolic profile compared survivors showing a significant discrimination with the use of GC-MS-based gastric fluid and urine analysis. Results of this study support the usefulness of metabolomics in developing survival biomarkers in very preterm infants.

Appropriate supplementation of vitamin D can affect infections, allergy, and mental and behavioral development. This study aimed to assess the effectiveness of monitored vitamin D supplementation in a population of preterm infants. 109 preterm infants (24 0/7–32 6/7 weeks of gestation) were randomized to receive 500 IU vitamin D standard therapy (n=55; approximately 800-1000 IU from combined sources) or monitored therapy (n=54; with an option of dose modification). 25(OH)D concentrations were measured at birth, 4 weeks of age, and 35, 40, and 52±2 weeks of post-conceptional age (PCA). Vitamin D supplementation was discontinued in 23% of infants subjected to standard treatment due to increased potentially toxic 25(OH)D concentrations (&gt;90 ng/mL) at 40 weeks of PCA. A significantly higher infants’ percentage in the monitored group had safe vitamin D levels (20–80 ng/mL) at 52 weeks of PCA (p=0.017). We observed increased vitamin D levels and abnormal ultrasound findings in five infants. Biochemical markers of vitamin D toxicity were observed in two patients at 52 weeks of PCA in the control group. Inadequate and excessive amounts of vitamin D can lead to serious health problems. Supplementation with 800–1000 IU of vitamin D prevents deficiency and should be monitored to avoid overdose.

Three-quarters of a million babies are born extremely preterm (< 28 weeks’ gestation) world-wide with devastating outcomes: 20% die in the newborn period, a further 35% develop bronchopul-monary dysplasia (BPD) and 10% suffer from cerebral palsy. Pioglitazone, a Peroxisome Proliferator Activated Receptor Gamma (PPARγ) agonist, may reduce the incidence of BPD and improve neurodevelopment in extreme preterm babies. Pioglitazone exerts an anti-inflammatory action mediated through Nuclear Factor-kappa B repression. PPARγ signalling is underactive in preterm babies as adiponectin remains low during the neonatal pe-riod. In newborn animal models, pioglitazone is shown to be protective against BPD, necrotising en-terocolitis, and lipopolysaccharide-induced brain injury. Single Nucleotide Polymorphisms of PPARγ are associated with inhibited preterm brain development and impaired neurodevelop-ment. Pioglitazone was well tolerated by the foetus in reproductive toxicology experiments. Bladder cancer, bone fractures, and macular oedema seen rarely in adults may be avoided with a short treatment course. Other effects of pioglitazone including improved glycaemic control and lipid metabolism may provide added benefit in prematurity. Currently, there is no formulation of pioglitazone suited for administration to preterm babies A liquid formulation of pioglitazone needs to be developed before clinical trials. The potential benefits are likely to outweigh any anticipated safety concerns.

This randomized control trial aims to test the hypothesis that twice-daily nurse-administered saline enema(SE) is comparable to physician-administrated SE in very low birth weight infants (VLBW) with meconium obstruction of prematurity (MOP). MOP is defined as no bowel opening for 48 h, and treatment failure is defined as the need for additional intervention and safety. Twice-daily SE was administered by accredited nurses, surgeons/neonatologists using standardized protocols. The outcomes were comparability of nurse to physician-administered SE in terms of frequency of administration, catheter insertion length and volume of enema, daily maximum meconium output, and treatment failure, defined as the need for additional intervention. Safety outcomes were evaluated. Twenty-eight infants were managed with SE. 389 SE were administered, 96 and 293 in 750-999g and 1000-1500g birth weight groups, respectively. Nurses administered 72.9% and 81.5% of SE in 750-999g and 1000-1500g birth weight groups, respectively. Physicians performed the rest of the SE. Daily meconium output was comparable in nurse and physician-administered SE in both groups. There were no treatment failures or adverse events in both SE group. SE administered by nurses was found to be comparable in terms of safety, efficacy, and frequency of administration to that of physician-administered SE.

Children with history of prematurity are at higher risk of complications, comorbidities and iron deficiency. In this study we assess the prevalence of restless sleep disorder, as well as that of periodic leg movements during sleep (PLMS) in these children. Retrospective chart review of sleep studies in children aged 1-18 years, with history of prematurity. Only diagnostic studies in children without diagnosis of a genetic syndrome or airway surgery or tracheostomy were included. Three groups were compared, children with PLMS index&gt;5, children with restless sleep disorder (RSD), and children with neither elevated PLMS index nor RSD. During the study, 2,577 sleep studies were conducted. Ninety-two studies fit our criteria and were included in analysis. Median birth age was 31 weeks, interquartile range (IQR) 27-34 weeks. Thirty-two (34.8%) children were referred for restless sleep and 55 (59.8%) for snoring; after polysomnography 18% were found to have PLMS index &gt;5/hour, 14% fit the criteria for RSD. There were no statistically significant differences in polysomnographic parameters between the children with RSD, PLMS and the remaining group, except for lower obstructive apnea/hypopnea index (Kruskal-Wallis ANOVA 8.621, p=0.0135) in the RSD group (median 0.7, IQR 0.3-0.9) than in the PLMS (median 1.7, IQR 0.7-3.5), or than in the nonRSD/nonPLMS group (median 2.0, IQR 0.8-4.5). There was elevated frequency of RSD and elevated PLMS in children with history of prematurity that might be linked to the increased risk of iron deficiency in premature infants. These new results add new knowledge on the prevalence of RSD in these children.

This study aimed evaluating 7 years’ outcome in 118 very preterm newborn (VPN, gestational age=26±1.4wks) involved in a randomized controlled trial. They presented neonatal respiratory distress (RDS) requiring ventilation for 14±2 days post-natal age (PNA). Repeated instillation of 200mg/kg Poractant alfa (SURF) did not improve early bronchopulmonary dysplasia, but SURF infants needed less re-hospitalization than controls for respiratory problem at 1- and 2-years PNA. There was no growth difference at 7.1±0.3 years for 41 SURF vs. 36 controls (80% eligible children); 7.9% SURF vs. 28.6% controls presented asthma (p=0.021). Children underwent cogni-tive assessment (WISC IV) and pulmonary function testing (PFT) measuring spirometry, lung volumes and airway resistance. Spirometry showed differences (p<0.05) between SURF and con-trols (mean±standard deviation (median z-score)) for FEV1 (L/s) (1.188±0.690(-0.803) vs. 1.080±0.243(-1.446)); FEV1 after betamimetics (1.244±0.183(-0.525) vs. 1.091±0.209(-1.342)); FVC (L) (1.402±0.217 (-0.406) vs. 1.265±0.267(-1.141)), and FVC after betamimetics 1.452±0.237 (-0.241) vs. 1.279±0.264(-1.020)). PFT showed no difference in volumes or airway resistance. Global IQ median [Inter-quartile Range] was 89[82:99] vs. 89[76:98] with 61% children >85 in both groups. Former VPN presenting severe neonatal RDS treated with repeated Surfactant have improved lung function and less asthma at 7 years PNA. There were no differences in neurodevelopmental outcome

Total Parenteral Nutrition (TPN), which uses intravenous administration of nutrients, minerals and vitamins, is essential in sustaining premature infants until they transition to enteral feeds. There is limited information on metabolomic differences between infants on TPN and enteral feeds. We performed untargeted global metabolomics on urine samples collected between 23-30 days of life from 314 infants born &lt;29 weeks gestational age from the TOLSURF and PROP cohorts. Principal component analysis across all metabolites showed a separation of infants solely on TPN as compared to infants who had transitioned to enteral feeds, indicating global metabolomic differences between infants based on feeding status. Among 913 metabolites that passed quality control filters, 609 varied in abundance between infants on TPN vs enteral feeds at p&lt;0.05. Of these, 88% were in the direction of higher abundance in the urine of infants on enteral feeds. In a subset of infants with longitudinal analysis, both concurrent and delayed changes in metabolite levels were observed with initiation of enteral feeds. Infants on enteral feeds had higher concentrations of essential amino acids, lipids, and vitamins, which are necessary for growth and development, suggesting a nutritional benefit of an enteral feeding regimen.

Antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or adverse pregnancy outcome in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPL). Preeclampsia (PE) complicates about 10-17% of pregnancies with APS. However, only early onset PE (< 34 weeks of gestation) belongs to the clinical criteria of APS. The similarities in the pathophysiology of early onset PE and APS emphasize an association of these two syndromes. Overall, both are the result of a defective trophoblast invasion and decidual transformation at early gestation. Women with APS are at increased risk for prematurity; the reasons are mostly iatrogenic due to placental dysfunction, such as PE or FGR. Interestingly, women with APS have also an increased risk for preterm delivery, even in the absence of FGR and PE and therefore not indicated but spontaneous. The basic treatment of APS in pregnancy is low-dose-aspirin and low-molecular- weight-heparin. Nevertheless, up to 20-30% of women develop complications at early and late gestation despite basic treatment. Several additional treatment options have been proposed, with Hydroxychloroquine (HCQ) being one of the most efficient. Additionally, nutritional interventions, such as intake of vitamin D have shown promising beneficial effects. Curcumin, due to its antioxidant and anti-inflammatory properties, might be considered as additional intervention as well.

Definitions of bronchopulmonary dysplasia (BPD) or post-prematurity respiratory disease (PPRD) aim to stratify the risk of mortality and morbidity, with an emphasis on long-term respiratory outcomes. There is no univocal classification of BPD, due to its complex multifactorial nature and the substantial heterogeneity of clinical presentation. Currently, there is no definitive cure available for extremely premature very-low-birth-weight infants with BPD, and challenges in finding targeted preventive therapies persist. However, innovative stem cells-based postnatal therapies targeting BPD-free survival are emerging, which are likely to be offered in the first few days of life to higher-risk subpopulations of premature infants. Hence the need for easy-to-use noninvasive tools for a standardized, precise and reliable BPD assessment at a very early stage, to support clinical decision-making and to predict the response to treatment. In this non-systematic review, we present an overview of strategies for monitoring preterm infants with early and evolving BPD-PPRD, and make some remarks on future prospects, with a focus on near-infrared spectroscopy (NIRS).

Background and Objectives: The purpose of this study was to assess the bleeding that occurs during the first weeks of gestation and its implications throughout pregnancy. Secondarily, we studied the associated complications that appeared and tried to identify possible risk factors that could serve to select women at a greater risk of adverse outcomes that could benefit from an early diagnosis and improved monitoring. Materials and Methods: We selected all the women who consulted for first trimester metrorrhagia in the Emergency Department of the Hospital QuirónSalud in Malaga over the year 2015. We refer to first trimester metrorrhagia as that which occurs until week 12+6. Once the pregnant women were identified, we studied certain risk factors already present prior to the gestation and others associated with the gestation and its evolution. Results: After reviewing the visits to the obstetrics and gynecology emergency department, we selected those patients that met the inclusion criteria, resulting in a sample of 696 patients that we followed up. The average age of our patients was 34.1 years, with an average number of visits to the hospital of 1.67, most of them between the 5th and 8th weeks of pregnancy. 45.3% of these pregnancies resulted in a first trimester miscarriage, mainly between weeks 6 and 8. We tried to establish associations in order to identify possible risk factors, finding a relationship between increased maternal age and a higher risk of first trimester pregnancy loss, which rises as maternal age increases (33,37 4,316 years vs 35,01 4,740 years). This increase in risk is proportional to the increase in age. We made subgroups of women over 35 and over 40 and confirmed that increased age led to worse outcomes. We also studied several gestational complications and concluded that they appeared more frequently among older women. These complications include prematurity (33.11 vs 34.48 years), gestational diabetes (33.11 vs 36.06 years) and preeclampsia (33.25 vs 35 years). We reviewed the obstetric history of pregnant women whose gestation resulted in miscarriage and found that 50.5% of them had previously had another loss. Conclusions: Comparing the results with data from the general population, we found that the rate of first trimester miscarriage is up to 3 times higher among women who present bleeding during the first weeks of gestation compared to those who do not develop this complication. Maternal age is a risk factor for first trimester pregnancy loss and for the development of complications associated with pregnancy.

A widely accepted concept is that boys are more susceptible than girls to oxidative stress related complications of prematurity, including bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and periventricular leukomalacia (PVL). We aimed to quantify the effect size of this male disadvantage by performing a systematic review and meta-analysis of cohort studies exploring the association between sex and complications of prematurity. Risk ratios (RRs) and 95% CIs were calculated by a random-effects model. Of 1365 potentially relevant studies, 41 met the inclusion criteria (625680 infants). Male sex was associated with decreased risk of hypertensive disorders of pregnancy, fetal distress, and C-section, but increased risk of low Apgar score, intubation at birth, respiratory distress, surfactant use, pneumothorax, postnatal steroids, late onset sepsis, any NEC, NEC&gt;stage 1 (RR 1.12, CI 1.06-1.18), any IVH, severe IVH (RR 1.28, CI 1.22-1.34), severe IVH or PVL, any BPD, moderate/severe BPD (RR 1.23, CI 1.18-1.27), severe ROP (RR 1.14, CI 1.07-1.22), and mortality (RR 1.23, CI 1.16-1.30). In conclusion, preterm boys have higher clinical instability and greater need for invasive interventions than preterm girls. This leads to a male disadvantage in mortality and short-term complications of prematurity.