Effects of Sepsis on Immune Response, Microbiome and Oxidative Metabolism in Preterm Infants.

This is a narrative review about the mechanisms involved in bacterial sepsis in preterm infants, which is an illness with a high incidence, morbidity, and mortality. The role of the innate immune response and its relationship with oxidative stress in the pathogenesis are described as well as their potential implementation as early biomarkers. Moreover, we address the impact that all the mechanisms triggered by sepsis have on the dysbiosis and the changes on neonatal microbiota.

Survey of transfusion practices in preterm infants in Europe.

BACKGROUND: Preterm infants commonly receive red blood cell (RBC), platelet and fresh frozen plasma (FFP) transfusions. The aim of this Neonatal Transfusion Network survey was to describe current transfusion practices in Europe and to compare our findings to three recent randomised controlled trials to understand how clinical practice relates to the trial data. METHODS: From October to December 2020, we performed an online survey among 597 neonatal intensive care units (NICUs) caring for infants with a gestational age (GA) of <32 weeks in 18 European countries. RESULTS: Responses from 343 NICUs (response rate: 57%) are presented and showed substantial variation in clinical practice. For RBC transfusions, 70% of NICUs transfused at thresholds above the restrictive thresholds tested in the recent trials and 22% below the restrictive thresholds. For platelet transfusions, 57% of NICUs transfused at platelet count thresholds above 25×109/L in non-bleeding infants of GA of <28 weeks, while the 25×109/L threshold was associated with a lower risk of harm in a recent trial. FFP transfusions were administered for coagulopathy without active bleeding in 39% and for hypotension in 25% of NICUs. Transfusion volume, duration and rate varied by factors up to several folds between NICUs. CONCLUSIONS: Transfusion thresholds and aspects of administration vary widely across European NICUs. In general, transfusion thresholds used tend to be more liberal compared with data from recent trials supporting the use of more restrictive thresholds. Further research is needed to identify the barriers and enablers to incorporation of recent trial findings into neonatal transfusion practice.

Early molecular markers of ventilator-associated pneumonia in bronchoalveolar lavage in preterm infants.

INTRODUCTION: Ventilator-associated pneumonia (VAP) constitutes a serious nosocomial infection. Our aim was to evaluate the reliability of cytokines and oxidative stress/inflammation biomarkers in bronchoalveolar lavage fluid (BALF) and tracheal aspirates (TA) as early biomarkers of VAP in preterm infants. METHODS: Two cohorts were enrolled, one to select candidates and the other for validation. In both, we included preterms with suspected VAP, according to BALF culture, they were classified into confirmed VAP and no VAP. Concentration of 16 cytokines and 8 oxidative stress/inflammation biomarkers in BALF and TA was determined in all patients. RESULTS: In the first batch, IL-17A and TNF-α in BALF, and in the second one IL-10, IL-6, and TNF-α in BALF were significantly higher in VAP patients. BALF TNF-α AUC in both cohorts was 0.86 (sensitivity 0.83, specificity 0.88). No cytokine was shown to be predictive of VAP in TA. A statistically significant increase in the VAP group was found for glutathione sulfonamide (GSA) in BALF and TA. CONCLUSIONS: TNF-α in BALF and GSA in BALF and TA were associated with VAP in preterm newborns; thus, they could be used as early biomarkers of VAP. Further studies with an increased number of patients are needed to confirm these results. IMPACT: We found that TNF-α BALF and GSA in both BALF and TA are capable of discriminating preterm infants with VAP from those with pulmonary pathology without infection. This is the first study in preterm infants aiming to evaluate the reliability of cytokines and oxidative stress/inflammation biomarkers in BALF and TA as early diagnostic markers of VAP. We have validated these results in two independent cohorts of patients. Previously studies have focused on full-term neonates and toddlers and determined biomarkers mostly in TA, but none was exclusively conducted in preterm infants.

Five-country manikin study found that neonatologists preferred using the LISAcath rather than the Angiocath for less invasive surfactant administration.

AIM: Less invasive surfactant administration (LISA) has been shown to decrease the risk of death and bronchopulmonary dysplasia in preterm neonates. The LISAcath is the first catheter to be specifically developed for LISA, and we compared the clinical impressions of neonatologists using the LISAcath and the commonly used Angiocath in a simulated setting. METHODS: This was a multinational, multicentre study, conducted in October 2016, which involved 39 neonatologists who were recruited by employees of the sponsor from large, well-recognised neonatal intensive care units across Europe. LISA was not the standard of care in these units in Austria, Belgium, Poland, Spain and the United Kingdom at the time of the study. After training, participants simulated LISA on a neonatal manikin, once with the LISAcath and once with Angiocath, then answered a 10-item questionnaire. RESULTS: The responses to nine of 10 questions showed that 67-95% of the respondents preferred the LISAcath to the Angiocath, with most of the remainder indicating no preference. The only exception was the luer connection question, with two-thirds expressing no preference. The LISAcath was considered potentially safer by 33 of 39 participants, with no votes for the Angiocath. CONCLUSION: Overall, neonatologists preferred using the LISAcath rather than the Angiocath on a neonatal manikin.

Oxygen needs during resuscitation and surfactant to achieve stabilisation were independent risks factors for pulmonary interstitial emphysema in preterm infants.

AIM: Pulmonary interstitial emphysema is a severe complication of mechanical ventilation in preterm infants that leads to air leakage and, or, chronic lung disease. We determined the associated risk factors. METHODS: This was a retrospective case-control study from 2005 to 2014 at a regional referral centre in Valencia, Spain. The cases were 54 preterm infants up to 30 weeks' gestation and, or, born weighing less than 1500 g, who were diagnosed with pulmonary interstitial emphysema (PIE). The 54 controls were preterm infants without PIE matched by gestational age. Univariate analysis and multivariate analysis were performed to assess the independent predicting factors. RESULTS: Infants with PIE had been resuscitated with higher mean fractional inspired oxygen concentration (FiO2 ) (p = 0.008), had received higher peak mean positive end expiratory pressure (p = 0.00) and higher mean airway pressure (p = 0.026) 24 hours before diagnosis. PIE patients also received more surfactant (p = 0.00) and had higher mortality (p = 0.034). A Cox regression model identified that independent risk factors were the total amount of surfactant administered and the mean FiO2 during the 24 hours before diagnosis. CONCLUSION: Independent risk factors for pulmonary interstitial emphysema in preterm infants were higher oxygen during resuscitation and a higher need for surfactant and ventilatory pressures before diagnosis.

Abdominal Near-Infrared Spectroscopy Detects Low Mesenteric Perfusion Early in Preterm Infants with Hemodynamic Significant Ductus Arteriosus.

BACKGROUND: The therapeutic decision to close patent ductus arteriosus in preterm infants entails great uncertainty. Near-infrared spectroscopy is a noninvasive bedside technique used to monitor mixed regional oxygen saturation. We hypothesized that near-infrared spectroscopy could identify preterm infants at risk of mesenteric hypoperfusion associated with hemodynamically significant ductus arteriosus. METHODS: This is a prospective observational study including consecutively admitted preterm infants with a gestational age <32 weeks. Mesenteric regional oxygenation was blindly monitored using an INVOS 5100 device. The presence of a hemodynamically significant patent ductus arteriosus was routinely confirmed by echocardiography/Doppler. Statistical analysis including Bland-Altman plots was performed to assess near-infrared spectroscopy intraobserver repeatability. RESULTS: A total of 72 preterm infants were enrolled. The daily mean regional oxygen saturation for preterm infants was determined both in mesenteric and cerebral regions and plotted against time. We identified a differential temporary baseline. Hemodynamic significant ductus arteriosus was associated with lower blood pressures and lower regional splanchnic oxygenation. There was a significant relationship between reversal diastolic flow in the descending aorta and the regional oxygen saturation, which remained significant after controlling for ductal size and nil per os. CONCLUSIONS: The simultaneous monitoring of splanchnic near-infrared spectroscopy and echocardiography could identify low mesenteric perfusion in the presence of hemodynamic ductus arteriosus.

Survival and Neurodevelopmental Outcomes of Preterms Resuscitated With Different Oxygen Fractions.

BACKGROUND AND OBJECTIVES: Stabilization of preterm infants after birth frequently requires oxygen supplementation. At present the optimal initial oxygen inspiratory fraction (Fio2) for preterm stabilization after birth is still under debate. We aimed to compare neurodevelopmental outcomes of extremely preterm infants at 24 months corrected age randomly assigned to be stabilized after birth with an initial Fio2 of 0.3 versus 0.6 to 0.65 in 3 academic centers from Spain and the Netherlands. METHODS: Randomized, controlled, double-blinded, multicenter, international clinical trial enrolling preterm infants <32 weeks' gestation assigned to an initial Fio2 of 0.3 (Lowox group) or 0.6 to 0.65 (Hiox group). During stabilization, arterial pulse oxygen saturation and heart rate were continuously monitored and Fio2 was individually titrated to keep infants within recommended ranges. At 24 months, blinded researchers used the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) to assess visual acuity, neurosensory deafness, and language skills. RESULTS: A total of 253 infants were recruited and 206 (81.4%) completed follow-up. No differences in perinatal characteristics, oxidative stress, or morbidities during the neonatal period were assessed. Mortality at hospital discharge or when follow-up was completed didn't show differences between the groups. No differences regarding Bayley-III scale scores (motor, cognitive, and language composites), neurosensorial handicaps, cerebral palsy, or language skills between groups were found. CONCLUSIONS: The use of an initial lower (0.3) or higher (0.6-0.65) Fio2 during stabilization of extremely preterm infants in the delivery room does not influence survival or neurodevelopmental outcomes at 24 months.

Neonatal assessment in the delivery room--Trial to Evaluate a Specified Type of Apgar (TEST-Apgar).

BACKGROUND: Since an objective description is essential to determine infant's postnatal condition and efficacy of interventions, two scores were suggested in the past but weren't tested yet: The Specified-Apgar uses the 5 items of the conventional Apgar score; however describes the condition regardless of gestational age (GA) or resuscitative interventions. The Expanded-Apgar measures interventions needed to achieve this condition. We hypothesized that the combination of both (Combined-Apgar) describes postnatal condition of preterm infants better than either of the scores alone. METHODS: Scores were assessed in preterm infants below 32 completed weeks of gestation. Data were prospectively collected in 20 NICU in 12 countries. Prediction of poor outcome (death, severe/moderate BPD, IVH, CPL and ROP) was used as a surrogate parameter to compare the scores. To compare predictive value the AUC for the ROC was calculated. RESULTS: Of 2150 eligible newborns, data on 1855 infants with a mean GA of 28(6/7) ± 2(3/7) weeks were analyzed. At 1 minute, the Combined-Apgar was significantly better in predicting poor outcome than the Specified- or Expanded-Apgar alone. Of infants with a very low score at 5 or 10 minutes 81% or 100% had a poor outcome, respectively. In these infants the relative risk (RR) for perinatal mortality was 24.93 (13.16-47.20) and 31.34 (15.91-61.71), respectively. CONCLUSION: The Combined-Apgar allows a more appropriate description of infant's condition under conditions of modern neonatal care. It should be used as a tool for better comparison of group of infants and postnatal interventions. TRIAL REGISTRATION: clinicaltrials.gov Protocol Registration System (NCT00623038). Registered 14 February 2008.

Urinary Lipid Peroxidation Byproducts: Are They Relevant for Predicting Neonatal Morbidity in Preterm Infants?

Preterm infants have an immature antioxidant system; however, they frequently require supplemental oxygen. Oxygen-free radicals cause both pulmonary and systemic inflammation, and they are associated with increased morbidity and mortality. Consequently, screening of metabolite profiles representing the amount of lipid peroxidation is considered of great relevance for the evaluation of in vivo oxidative stress and derived inflammation and damage. Ranges for total relative contents of isoprostanes (IsoPs), isofurans (IsoFs), neuroprostanes (NeuroPs), and neurofurans (NeuroFs) within targeted SpO2 ranges were determined in urine samples of 254 preterm infants<32 weeks of gestation within the frame of two randomized, controlled, and blinded clinical trials employing ultra-performance liquid chromatography-tandem mass spectrometry. A total of 536 serial urine samples collected during the first 4 weeks after birth in recruited infants who did not develop free radical associated conditions were analyzed. A reference range for lipid peroxidation byproducts, including isoprostanes, isofurans, neuroprostanes, and neurofurans, was calculated and possible correlations with neonatal conditions were investigated. Urinary elimination of isofurans in the first 4 days after birth correlated with later development of bronchopulmonary dysplasia. Our observations lead to the hypothesis that early urinary determination of lipid peroxidation byproducts, especially isofurans, is relevant to predict development of chronic lung conditions.

Administration of surfactant using less invasive techniques as a part of a non-aggressive paradigm towards preterm infants.

Traditional treatment of respiratory distress syndrome in preterm infants consisted of early intubation, mechanical ventilation and intra-tracheal administration of exogenous surfactant. Recently, non-invasive ventilation, which has shown some advantages in short- and long-term outcomes, has gained popularity for the initial management of respiratory insufficiency in preterm infants. However, non-invasive ventilation from the outset poses difficulties in relation to administration of exogenous surfactant. The customary INSURE technique requires tracheal intubation, surfactant administration, and rapid extubation, but the latter is not always possible. As a more elegant approach, several minimally invasive techniques of delivering surfactant have been developed for babies spontaneously breathing on CPAP. The most extensively studied have been those in which the trachea is briefly catheterized with a nasogastric tube or vascular catheter, and exogenous surfactant is administered. Although results seem promising they are not yet conclusive, and further studies will be needed to answer a number of outstanding questions.

Systematic review and meta-analysis of optimal initial fraction of oxygen levels in the delivery room at ≤32 weeks.

AIM: The optimal initial fraction of oxygen (iFiO2 ) for resuscitating/stabilising premature infants is not known. We aimed to study currently available information and provide guidelines regarding the iFiO2 levels needed to resuscitate/stabilise premature infants of ≤32 weeks' gestation. METHODS: Our systematic review and meta-analysis studied the effects of low and high iFiO2 during the resuscitation/stabilisation of 677 newborn babies ≤32 weeks' gestation. RESULTS: Ten randomised studies were identified covering 321 infants receiving low (0.21-0.30) iFiO2 levels and 356 receiving high (0.60-1.0) levels. Relative risk for mortality was 0.62 (95% CI: 0.37-1.04, I(2) = 0%, p(heterogeneity) = 0.88) for low versus high iFiO2 ; for bronchopulmonary dysplasia, it was 1.11 (95% CI: 0.73-1.68, I(2) = 46%, p(heterogeneity) = 0.06); and for intraventricular haemorrhage, it was 0.90 (95% CI: 0.53-1.53, I(2) = 9%, p(heterogeneity) = 0.36). CONCLUSION: These data show that reduced mortality approached significance when a low iFiO2 (0.21-0.30) was used for initial stabilisation, compared to a high iFiO2 (0.60-1.0). There was no significant association for bronchopulmonary dysplasia or intraventricular haemorrhage when comparing low and high iFiO2 . Based on present data, premature babies ≤32 weeks' gestation in need of stabilisation in the delivery room should be given an iFiO2 of 0.21-0.30.

Minimally invasive surfactant therapy with a gastric tube is as effective as the intubation, surfactant, and extubation technique in preterm babies.

AIM: Preterm infants requiring surfactant replacement have been treated using the INSURE technique, which requires sedation and comprises tracheal intubation, surfactant instillation and extubation. However, minimally invasive surfactant therapy (MIST) does not require sedation, minimises airway injury and avoids placing positive pressure ventilation on an immature lung. This study compared the feasibility of the two techniques and the outcomes in preterm babies with respiratory distress syndrome (RDS). METHODS: Preterm infants with RDS prospectively received surfactant via a gastric tube placed in the trachea by direct laryngoscopy with no sedation. Technique-related complications and respiratory outcomes were analysed. RESULTS: We compared 44 patients who received MIST with a historic cohort of 31 patients who received INSURE. This showed no differences in the rate of intubation and mechanical ventilation in the first 72 h, or secondary respiratory outcomes and relevant morbidities, between the babies who received INSURE and those who received MIST. More babies in the MIST group (35%) needed a second dose of surfactant than the INSURE group (6.5%) (p < 0.0001). CONCLUSION: Surfactant administration using MIST, with no sedation, is feasible in preterm infants with RDS. No significant differences in secondary respiratory outcomes were found between the MIST and INSURE techniques.

Cervical IL-6 and pIGFBP-1 and the prediction of neonatal outcome in symptomatic preterm labour.

OBJECTIVE: To evaluate the use of cervical Interleukin 6 (IL-6) and phosphorylated Insulin Growth Binding Protein 1 (pIGFBP1) in the prediction of adverse neonatal outcome. METHODS: Prospective observational study including women between 24 and 34 weeks of gestation. One hundred and twelve cervical samples for IL-6 and pIFBP1 were taken. Neonatal outcome variables were birth weight, Apgar scores at 1st/5th minute, gestational age at delivery, admission to neonatal unit (NNU) and to neonatal intensive care unit (NICU), composite neonatal morbidity (NCM) and neonatal mortality. RESULTS: Cervical IL-6 concentrations (pg/ml) were higher in neonates admitted to NNU and NICU versus non-admission, and women developing chorioamnionitis versus non-chorioamnionitis (mean ± standard deviation: 168.1 ± 205.2 versus 62.3 ± 72.4, p < 0.01; 262.1 ± 298 versus 92 ± 127.6, p < 0.01, and 564 ± 213 versus 93.4 ± 126.4, p < 0.05, respectively). In the NCM group, the IL-6 concentrations were higher compared to the non-NCM (181.7 ± 224 versus 84.1 ± 117.7, p < 0.05). In the preterm births <37 weeks, no differences were found for NCM, admission to NICU/NNU. The logistic regression analysis, showed cervical IL-6 and examination-to-delivery interval as predictors of NCM in the univariate analysis. However, the only independent marker of adverse neonatal outcome was the examination-to-delivery interval. CONCLUSIONS: Adverse neonatal outcome is associated with increased cervical IL-6 concentrations.

Oxygen in the delivery room.

Immediately after birth the newly born infant aerates the lungs, diminishes pulmonary vascular resistance, and initiates gas exchange. However, under certain circumstances this process will not be adequately accomplished. Asphyxia is characterized by periods of hypoxia and ischemia leading frequently to hypoxic ischemic encephalopathy. The mainstay of newborn resuscitation resides in the establishment of a functional residual capacity and an adequate oxygenation. Recent guidelines have established guidelines which provide counsel on the use of oxygen in term infants. However, preterm oxygenation in the delivery room (DR) has only been defined very vaguely. Herewith, we will address available information regarding the use of oxygen supplementation in the DR both in term and preterm babies for a satisfactory postnatal adaptation.

Ventilator-associated pneumonia in newborn infants diagnosed with an invasive bronchoalveolar lavage technique: a prospective observational study.

OBJECTIVES: To establish the incidence, etiology, risk factors, and outcomes associated with ventilator-associated pneumonia using an invasive sampling technique to avoid contamination. PATIENTS: Eligible patients were intubated neonates treated with mechanical ventilation who followed the criteria of the Centers for Disease Control and Prevention/National Nosocomial Infection Surveillance. Bronchoalveolar lavage samples were collected using a blind-protected catheter to avoid contamination of upper respiratory microorganisms. Isolation of >10(3) colony-forming unit/mL was required for diagnosis. MEASUREMENTS AND MAIN RESULTS: In 198 neonates intubated for >48 hrs, a total of 18 episodes of ventilator-associated pneumonia in 16 infants representing a prevalence of 8.1 were diagnosed. The pooled mean ventilator-associated pneumonia rate was 10.9/1,000 ventilator days. The mean age at diagnosis of ventilator-associated pneumonia was 29 ± 15 days after a mean of 21 ± 16 days of mechanical ventilation. Gram-negative bacteria were the most commonly isolated pathogens and Pseudomonas aeruginosa was the most frequent causative agent. Hospital length of stay was significantly longer for ventilator-associated pneumonia patients; however, no significant differences in mortality were found. Univariate analysis comparing patients with and without ventilator-associated pneumonia showed that days of mechanical ventilation, days of oxygen, number of reintubations, number of transfusions, bloodstream infection, and enteral feeding were all significantly associated with ventilator-associated pneumonia. However, in multivariate analysis the unique independent risk factor was days of mechanical ventilation (odds ratio 1.12, confidence interval 95% 1.07-1.17). CONCLUSIONS: Ventilator-associated pneumonia is a frequent nosocomial infection in newborns. Only duration of mechanical ventilation has been identified as an independent risk factor for ventilator-associated pneumonia. The use of a blind invasive sampling technique seems to diminish sample contamination.

Oxygen saturation after birth in preterm infants treated with continuous positive airway pressure and air: assessment of gender differences and comparison with a published nomogram.

AIMS: The goal of the study was to compare preductal SpO2 in the first 10 min after birth in preterm infants treated with non-invasive continuous positive airway pressure (CPAP) and air with a published nomogram of preductal SpO2 in preterm infants who received no medical intervention, and to examine gender differences. DESIGN: Prospective observational study. PATIENTS AND METHODS: We enrolled infants of ≤32 weeks gestation who were spontaneously breathing with heart rate >100 bpm, and treated with face mask CPAP and air during postnatal stabilisation. SpO2 limits were targeted at ≥75% at 5 min and ≥85% at 10 min and heart rate at >100 bpm. FIO2 was titrated against SpO2. Preductal SpO2, airway pressure and FIO2 were recorded with a data acquisition system from birth until stabilisation. Babies receiving supplemental oxygen (>21%), positive pressure ventilation, were intubated and/or received chest compressions or drugs were excluded. RESULTS: Measurements were obtained in 102 babies with median gestational age of 29 (range: 24-31) weeks. Median SpO2 was significantly higher in the observational group than in the reference range at 3 min (82% (CI 71% to 85%) vs 76% (CI 67% to 83%); p<0.05), at 4 min (87% (CI 81% to 90%) vs 81% (CI 72% to 88%); p<0.05), at 5 min (92% (CI 88% to 95%) vs 86% (CI 80% to 92%); p<0.05), at 6 min (94% (CI 90% to 97%) vs 90% (CI 81% to 95%); p<0.05), at 7 min (95% (CI 92% to 97%) vs 92% (CI 85% to 95%); p<0.05), at 8 min (96% (CI 93% to 98%) vs 92% (CI 87% to 96%); p<0.05) and at 9 min (97% (CI 92% to 99%) vs 93% (CI 87% to 96%); p<0.05). Female babies achieved targeted SpO2 significantly earlier than male babies. CONCLUSIONS: Preterm babies receiving CPAP and air and especially female subjects achieve reference oxygen saturation more rapidly than spontaneously breathing preterm babies without respiratory aid.

Oxygen saturation targets for preterm infants in the delivery room.

Fetal life evolves in a low oxygen milieu as compared to the extra-uterine. In the fetal to neonatal transition rapid changes in the oxygen content of the newly born infant occur within a brief period of time. Delivery room care givers should be aware of the slow transition regarding oxygenation, and supply oxygen as needed trying to avoid damage caused by hyper-and-hypoxia. In this regard, titrating oxygen inspiratory fraction against oxygen saturation as measured by pulse oximetry following recent nomogram ranges is a valid method.

The use and misuse of oxygen during the neonatal period.

This article describes aerobic metabolism, oxygen free radicals, antioxidant defenses, oxidative stress, inflammatory response and redox signaling, the fetal to neonatal transition, arterial oxygen saturation, oxygen administration in the delivery room, oxygen during neonatal care in the NICU, evolving oxygen needs in the first few weeks of life, and complications that can occur when infants go home from the hospital on oxygen.

Antenatal steroids and antioxidant enzyme activity in preterm infants: influence of gender and timing.

Antenatal steroids have improved the survival of preterm infants; however, the mechanism of action is not fully understood. We aimed to establish an association between antenatal steroids and antioxidant activity and postnatal oxidative stress. In a prospective cohort study, extremely preterm neonates receiving antenatal steroids (CORT) or not (NOCORT) were enrolled. An association between antenatal steroids and activities of antioxidant enzymes and glutathione cycle enzymes in cord blood was found. In addition, reduced oxidative stress (GSH/GSSG ratio, CORT vs. NOCORT, 35.68 + or - 12.20 vs. 28.38 + or - 9.92; p < 0.01) and, decreased oxidation of proteins (ortho-tyrosine/phenylalanine ratio, CORT vs. NOCORT, 8.66 + or - 2.45 vs. 12.55 + or - 4.41; p < 0.01) and DNA (8oxodG/2dG ratio, CORT vs. NOCORT, 6.73 + or - 2.18 vs. 9.53 + or - 3.83; p < 0.01) also was found. Antenatal steroids were associated with reduced oxygen supplementation, mechanical ventilation, and conditions such as bronchopulmonary dysplasia, intra-periventricular hemorrhage, or retinopathy of prematurity. The maximal effectiveness was when steroids were administered 2-4 days before delivery. Female preterm infants had less oxidative stress and increased antioxidant activity and better clinical outcomes than did male infants, independent of receiving or not antenatal steroids. Antenatal steroids are accompanied by a reduction in postnatal oxidative-stress-derived conditions and increased antioxidant enzyme activity. Both these effects seem to be influenced by specific timing and female gender.