Vaginal Progesterone to Prevent Spontaneous Preterm Birth in Women With a Sonographic Short Cervix: The Story of the PREGNANT Trial.

The PREGNANT trial was a randomized, placebo-controlled, multicenter trial designed to determine the efficacy and safety of vaginal progesterone (VP) to reduce the risk of birth < 33 weeks and of neonatal complications in women with a sonographic short cervix (10 to 20 mm) in the mid-trimester (19 to 23 6/7 wk). Patients allocated to receive VP had a 45% lower rate of preterm birth (8.9% vs 16.1%; relative risk = 0.55; 95% CI: 0.33-0.92). Neonates born to mothers allocated to VP had a 60% reduction in the rate of respiratory distress syndrome. This article reviews the background, design, execution, interpretation, and impact of the PREGNANT Trial.

Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome.

BACKGROUND: Laryngeal mask airway surfactant administration (S-LMA) has the potential benefit of surfactant administration whilst avoiding endotracheal intubation and ventilation, ventilator-induced lung injury and bronchopulmonary dysplasia (BPD). OBJECTIVES: To evaluate the benefits and harms of S-LMA either as prophylaxis or treatment (rescue) compared to placebo, no treatment, or intratracheal surfactant administration via an endotracheal tube (ETT) with the intent to rapidly extubate (InSurE) or extubate at standard criteria (S-ETT) or via other less-invasive surfactant administration (LISA) methods on morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome (RDS). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trial registries in December 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster- or quasi-RCTs of S-LMA compared to placebo, no treatment, or other routes of administration (nebulised, pharyngeal instillation of surfactant before the first breath, thin endotracheal catheter surfactant administration or intratracheal surfactant instillation) on morbidity and mortality in preterm infants at risk of RDS. We considered published, unpublished and ongoing trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included eight trials (seven new to this update) recruiting 510 newborns. Five trials (333 infants) compared S-LMA with surfactant administration via ETT with InSurE. One trial (48 infants) compared S-LMA with surfactant administration via ETT with S-ETT, and two trials (129 infants) compared S-LMA with no surfactant administration. We found no studies comparing S-LMA with LISA techniques or prophylactic or early S-LMA. S-LMA versus surfactant administration via InSurE S-LMA may have little or no effect on the composite outcome of death or BPD at 36 weeks' postmenstrual age (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.27 to 8.34, I 2 = not applicable (NA) as 1 study had 0 events; risk difference (RD) 0.02, 95% CI -0.07 to 0.10; I 2 = 0%; 2 studies, 110 infants; low-certainty evidence). There may be a reduction in the need for mechanical ventilation at any time (RR 0.53, 95% CI 0.36 to 0.78; I 2 = 27%; RD -0.14, 95% CI -0.22 to -0.06, I 2 = 89%; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 5 to 17; 5 studies, 333 infants; low-certainty evidence). However, this was limited to four studies (236 infants) using analgesia or sedation for the InSurE group. There was little or no difference for air leak during first hospitalisation (RR 1.39, 95% CI 0.65 to 2.98; I 2 = 0%; 5 studies, 333 infants (based on 3 studies as 2 studies had 0 events); low-certainty evidence); BPD among survivors to 36 weeks' PMA (RR 1.28, 95% CI 0.47 to 3.52; I 2 = 0%; 4 studies, 264 infants (based on 3 studies as 1 study had 0 events); low-certainty evidence); or death (all causes) during the first hospitalisation (RR 0.28, 95% CI 0.01 to 6.60; I 2 = NA as 2 studies had 0 events; 3 studies, 203 infants; low-certainty evidence). Neurosensory disability was not reported. Intraventricular haemorrhage ( IVH) grades III and IV were reported among the study groups (1 study, 50 infants). S-LMA versus surfactant administration via S-ETT No study reported death or BPD at 36 weeks' PMA. S-LMA may reduce the use of mechanical ventilation at any time compared with S-ETT (RR 0.47, 95% CI 0.31 to 0.71; RD -0.54, 95% CI -0.74 to -0.34; NNTB 2, 95% CI 2 to 3; 1 study, 48 infants; low-certainty evidence). We are very uncertain whether S-LMA compared with S-ETT reduces air leak during first hospitalisation (RR 2.56, 95% CI 0.11 to 59.75), IVH grade III or IV (RR 2.56, 95% CI 0.11 to 59.75) and death (all causes) during the first hospitalisation (RR 0.17, 95% CI 0.01 to 3.37) (1 study, 48 infants; very low-certainty evidence). No study reported BPD to 36 weeks' PMA or neurosensory disability. S-LMA versus no surfactant administration Rescue surfactant could be used in both groups. There may be little or no difference in death or BPD at 36 weeks (RR 1.65, 95% CI 0.85 to 3.22; I 2 = 58%; RD 0.08, 95% CI -0.03 to 0.19; I 2 = 0%; 2 studies, 129 infants; low-certainty evidence). There was probably a reduction in the need for mechanical ventilation at any time with S-LMA compared with nasal continuous positive airway pressure without surfactant (RR 0.57, 95% CI 0.38 to 0.85; I 2 = 0%; RD -0.24, 95% CI -0.40 to -0.08; I 2 = 0%; NNTB 4, 95% CI 3 to 13; 2 studies, 129 infants; moderate-certainty evidence). There was little or no difference in air leak during first hospitalisation (RR 0.65, 95% CI 0.23 to 1.88; I 2 = 0%; 2 studies, 129 infants; low-certainty evidence) or BPD to 36 weeks' PMA (RR 1.65, 95% CI 0.85 to 3.22; I 2 = 58%; 2 studies, 129 infants; low-certainty evidence). There were no events in either group for death during the first hospitalisation (1 study, 103 infants) or IVH grade III and IV (1 study, 103 infants). No study reported neurosensory disability. AUTHORS' CONCLUSIONS: In preterm infants less than 36 weeks' PMA, rescue S-LMA may have little or no effect on the composite outcome of death or BPD at 36 weeks' PMA. However, it may reduce the need for mechanical ventilation at any time. This benefit is limited to trials reporting the use of analgesia or sedation in the InSurE and S-ETT groups. There is low- to very-low certainty evidence for no or little difference in neonatal morbidities and mortality. Long-term outcomes are largely unreported. In preterm infants less than 32 weeks' PMA or less than 1500 g, there are insufficient data to support or refute the use of S-LMA in clinical practice. Adequately powered trials are required to determine the effect of S-LMA for prevention or early treatment of RDS in extremely preterm infants. S-LMA use should be limited to clinical trials in this group of infants.

Surfactant delivery strategies to prevent bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is one of the most devastating morbidities of preterm infants. Antenatal factors like growth restriction and inflammation are risk factors for its development. Use of oxygen and positive pressure ventilation, which are often necessary to treat respiratory distress syndrome (RDS), increase the risk for development of BPD. Continuous positive airway pressure (CPAP) as primary respiratory support allows for avoidance of positive pressure ventilation in many cases but may lead to a delay of surfactant administration which is a proven therapy for RDS. Several alternative surfactant delivery strategies, including nebulization of surfactant, pharyngeal instillation of surfactant, delivery of surfactant via supraglottic airway device or surfactant delivery via a thin endotracheal catheter have been described which allow for the benefit of surfactant therapy while on CPAP. This review reports available data and discusses the existing evidence of their value in preventing BPD as well as further research directions.

Surfactant therapy guided by tests for lung maturity in preterm infants at risk of respiratory distress syndrome.

BACKGROUND: Administration of various exogenous surfactant preparations has been shown to decrease lung injury and pneumothorax and improve survival in very preterm infants with respiratory distress syndrome (RDS). There is no consensus on the threshold for surfactant administration, to allow timely intervention and avoid over-treatment, also considering the invasiveness of the procedure and its cost. Rapid tests for lung maturity, which include the click test, lamellar body counts and stable microbubble test, might guide the identification of those infants needing surfactant administration. OBJECTIVES: To assess the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants at risk for or having RDS. Comparison 1: In preterm infants at risk for RDS, does surfactant treatment guided by rapid tests for surfactant deficiency compared to prophylactic surfactant administration to all high-risk infants minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality? Comparison 2: In preterm infants who require early respiratory support, does surfactant treatment guided by rapid tests for surfactant deficiency compared to surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality? SEARCH METHODS: We searched in October 2022 CENTRAL, PubMed, Embase and three additional trial registries. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs evaluating rapid tests after birth for surfactant deficiency in infants at high risk of RDS or requiring respiratory support. We specified two comparisons: 1)surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high-risk infants in extremely preterm (less than 28 weeks' gestation) and very preterm (28 to 32 weeks' gestation); 2)surfactant treatment guided by rapid tests for surfactant deficiency versus surfactant therapy provided to preterm infants (less than 37 weeks' gestation) with RDS diagnosed on clinical and radiologic criteria. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) and risk difference (RD), with their 95% confidence intervals (CIs) for dichotomous data. Our primary outcomes were: neonatal mortality, mortality prior to hospital discharge, bronchopulmonary dysplasia and the composite outcome bronchopulmonary dysplasia or mortality. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included three RCTs enrolling 562 newborn infants in this review. No studies compared surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high-risk infants. Comparing surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported neonatal mortality. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge: RR 1.25, 95% CI 0.65 to 2.41, RD 0.01, 95% CI -0.03 to 0.05, 562 participants, 3 studies; I² for RR and RD = 75% and 43%, respectively; very low-certainty evidence. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia: RR 0.90, 95% CI 0.61 to 1.32, RD -0.02, 95% CI -0.08 to 0.04, 562 participants, 3 studies; I² for RR and RD = 0%; low-certainty evidence. No studies reported the composite outcome bronchopulmonary dysplasia or mortality. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in surfactant utilization (RR 0.97, 95% CI 0.85 to 1.11, RD -0.02, 95% CI -0.10 to 0.06, 562 participants, 3 studies, I² for RR and RD = 63% and 65%, respectively, low-certainty evidence), and any pneumothorax (RR 0.53, 95% CI 0.15 to 1.92, RD -0.01, 95% CI -0.04 to 0.01, 506 participants, 2 studies, I² for RR and RD = 0%, low-certainty evidence) compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported moderate to severe neurodevelopmental impairment. We identified two large ongoing RCTs. AUTHORS' CONCLUSIONS: No studies compared surfactant treatment guided by rapid tests for surfactant deficiency to prophylactic surfactant administration to all high-risk infants. Low to very low-certainty evidence from three studies is available on surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported neonatal mortality, the composite outcome 'bronchopulmonary dysplasia or mortality', or neurodevelopmental outcomes. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia, surfactant utilization and any pneumothorax. The findings of the two large ongoing trials identified in this review are likely to have an important impact on establishing the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants.

One vs 2 courses of antenatal corticosteroids in pregnancies at risk of preterm birth: a secondary analysis of the MACS trial.

BACKGROUND: Birth is unpredictable and many patients who receive antenatal corticosteroids for preterm birth remain pregnant. Some professional societies recommend rescue antenatal corticosteroids for those who remain pregnant ≥14 days following the initial course. OBJECTIVE: This study aimed to explore a single vs a second course of antenatal corticosteroids in terms of severe neonatal morbidity and mortality. STUDY DESIGN: This is a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth (MACS) trial. The MACS study was a randomized clinical trial conducted in 80 centers in 20 different countries from 2001 to 2006. Participants who received only 1 course of intervention (ie, either a second course of antenatal corticosteroids or placebo) were included in this study. The primary outcome was a composite of stillbirth, neonatal mortality in the first 28 days of life or before discharge, severe respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage stage III and IV, periventricular leukomalacia, and necrotizing enterocolitis. Two subgroup analyses were planned to address the effect of a second course of antenatal corticosteroids on infants born before 32 weeks or within 7 days from the intervention. Moreover, a sensitivity analysis was performed to assess the effect of intervention on singleton pregnancies. Baseline characteristics were compared between the groups using chi-square and Student t tests. Multivariable regression analysis was performed to adjust for confounding variables. RESULTS: There were 385 and 365 participants included in the antenatal corticosteroid and placebo groups, respectively. The composite primary outcome occurred in 24% and 20% of participants in the antenatal corticosteroid and placebo groups, respectively (adjusted odds ratio, 1.09; 95% confidence interval, 0.76-1.57). Moreover, severe respiratory distress syndrome rate was similar between the 2 groups (adjusted odds ratio, 0.98; 95% confidence interval, 0.65-1.48). Newborns exposed to antenatal corticosteroids were more likely to be small for gestational age (14.9% vs 10.6%; adjusted odds ratio, 1.63; 95% confidence interval, 1.07-2.47). These findings remained true among singleton pregnancies for the primary composite outcome and birthweight <10th percentile (adjusted odds ratio, 1.29 [0.82-2.01]; and adjusted odds ratio, 1.74 [1.06-2.87]; respectively). Subgroup analyses of infants born before 32 weeks or within 7 days from the intervention did not show any benefits in terms of the composite primary outcome with antenatal corticosteroids vs placebo (50.5% vs 41.8% [adjusted odds ratio, 1.16; 95% confidence interval, 0.78-1.72]; and 42.3% vs 37.1% [adjusted odds ratio, 1.02; 95% confidence interval, 0.67-1.57]; respectively). CONCLUSION: Neonatal mortality and severe morbidities, including severe respiratory distress syndrome, were not improved by a second course of antenatal corticosteroids. Policy makers need to be thoughtful when recommending a second course of antenatal corticosteroids and consider whether not only short-term but also long-term benefits can be gained from such administration.

A randomized clinical trial of antibiotic treatment duration in preterm pre-labor rupture of membranes: 7 days vs until delivery.

BACKGROUND: Antibiotic treatment in preterm pre-labor rupture of membranes can prolong the interval from membrane rupture to delivery and improve neonatal outcomes. However, the duration of antibiotic treatment for preterm pre-labor rupture of membranes has been rarely compared in prospective studies. OBJECTIVE: This study aimed to investigate the optimal duration of antibiotic treatment for pre-labor rupture of membranes. We performed a randomized controlled trial comparing neonatal morbidity and infantile neurologic outcomes between 2 groups of patients with preterm pre-labor rupture of membranes who received antibiotic treatment for 7 days or until delivery, respectively. STUDY DESIGN: This prospective randomized study included patients who were diagnosed with preterm pre-labor rupture of membranes between 22+0 weeks and 33+6 weeks of gestation. The enrolled patients were randomly assigned to receive intravenous cefazolin (1 g dosage every 12 hours) and oral clarithromycin (500 mg dosage every 12 hours) either for 7 days or until delivery. The study protocol was registered at ClinicalTrials.gov under identifier NCT01503606. The primary outcome was a neonatal composite morbidity, and the secondary outcome was neurologic outcomes at 12 months of corrected age. We enrolled 151 patients and allocated 75 and 76 of them to the 7-day and until-delivery groups, respectively. Analysis was done by per protocol. RESULTS: After excluding cases lost to follow-up and those with protocol violations, 63 (7-day regimen) and 61 (until-delivery regimen) patients with preterm pre-labor rupture of membranes and their babies were compared. There was no significant difference in the pregnancy outcomes, including gestational age at delivery and the interval from rupture of membranes to delivery, between the 2 groups. Among the neonatal outcomes, bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity, necrotizing enterocolitis, and proven neonatal sepsis did not differ between the groups. However, the rates of respiratory distress syndrome (32.8% vs 50.8%; P=.039) and composite neonatal morbidities (34.4% vs 53.9%; P=.026) were lower in the until-delivery group than in the 7-day group. This difference remained statistically significant after a multivariable analysis adjusting for maternal age, twin pregnancy, antenatal corticosteroids treatment, gestational age at delivery, interval from rupture of membranes to delivery, and clinical chorioamnionitis. Infantile neurologic outcomes were evaluated in 71.4% of the babies discharged alive and did not differ between the groups. CONCLUSION: Overall, the until-delivery regimen of cefazolin and clarithromycin in preterm pre-labor rupture of membranes led to a lower incidence of composite neonatal morbidity and respiratory distress syndrome than the 7-day regimen, and both regimens otherwise showed similar individual neonatal morbidities and infantile neurologic outcomes.

Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome. METHODS: We designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks' gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076. FINDINGS: Between Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI -0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI -0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3-4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia. INTERPRETATION: Because non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction. FUNDING: French Ministry of Health.

Concentración de lactato deshidrogenasa en grupos de edad pediátrica diferentes / Lactate dehydrogenase concentration in different pediatric age groups

La normalización del nivel de LDH en sangre se asocia con una mejor supervivencia en muchos estudios realizados en adultos, en niños y recién nacidos. El estudio tuvo como objetivo estimar la LDH para diferentes grupos de edad de pediatría. Se realizó un estudio observacional en Pediatrics Ward, Hospital General de Abu Ghraib, de enero de 2018 a diciembre de 2019. La muestra de estudio incluyó a 250 niños, su edad osciló entre 1 día y 16 años. Se calcularon los niños de ambos género con estos grupos de edad admitidos en Ward, y se calcularon LDH en sangre. La historia materna, la fiebre, la infección umbilical, la sollozo, la hipoxia, la sepsis y el síndrome de dificultad respiratoria (RDS) se documentaron en consecuencia. LDH medido como siguió: Recién nacido: 160 a 450 unidades por litro (unidades/L) y niño: 60 a 170 unidades/l. Dividimos la muestra a dos grupos, bebés recién nacidos (1 día a 1 año) y CHID (> 1 año a 16 años), y se documentaron las variables de estudio. La correlación de concentración y variables de LDH calculada. Se confirma el valor pronóstico del monitoreo de LDH en suero en serie para predecir la morbilidad y la mortalidad en los niños enfermos. Hay una correlación, aunque muy clara, entre los niveles de LDH en plasma con infección, asfixia y RDS

Normalisation of blood LDH level is associated with improved survival in many studies conducted in adults, in children and neonate. The study aimed to estimate the LDH for different pediatrics age groups. An observational study was conducted at Pediatrics ward, Abu Ghraib General Hospital, from January 2018 to December 2019. Study sample included 250 children; their age ranged from 1 day to 16 years. Children of both gender with these age groups admitted to ward, and blood LDH were calculated. The maternal history, fever, umbilical infection, SOB, hypoxia, sepsis, and respiratory distress syndrome (RDS) were documented accordingly. LDH measured as followed: New born: 160 to 450 units per litre (units/L) and child: 60 to 170 units/L. We divided sample to two-groups, newborn babies (1 day to 1 year) and chid (>1 year to 16 years), and the study variables were documented. The LDH concentration and variables correlation calculated. The prognostic value of serial serum LDH monitoring for predicting morbidity and mortality in sick children is confirmed. There is a correlation, although very clear, between the plasma LDH levels with infection, asphyxia, and RDS

Antenatal Corticosteroids and Neonatal Outcomes in Twins: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess whether antenatal corticosteroid treatment is associated with improved neonatal outcomes in twins. DATA SOURCES: We searched MEDLINE, PubMed, EMBASE, and the Cochrane Library, from inception through August 12, 2021. We did not search ClinicalTrials.gov because our inclusion criteria were restricted to nonrandomized studies. METHODS OF STUDY SELECTION: Records (n=7,802) were screened in Rayyan by two independent reviewers. We included all nonrandomized studies that compared antenatal corticosteroid treatment with no treatment in twins. Our outcomes of interest were neonatal mortality, respiratory distress syndrome (RDS), intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, periventricular leukomalacia, and retinopathy of prematurity. TABULATION, INTEGRATION, AND RESULTS: We used the ROBINS-I tool (Risk Of Bias In Non-randomised Studies - of Interventions) to assess risk of bias. We performed random-effects meta-analyses of estimates from studies without critical risk of bias due to confounding, and reported summary adjusted odds ratios (aORs) and 95% CIs. Eighteen cohort studies (that reported on 33,152 neonates) met inclusion criteria. Sixteen studies restricted to preterm gestational ages, and 11 defined exposed neonates based on an optimal corticosteroid administration-to-birth interval. Limitations due to confounding and selection bias were common concerns for the risk-of-bias assessments (n=14 at critical or higher), and 11 studies did not account for clustering within twin pairs in their analyses. All included studies had at least moderate risk of bias. Meta-analysis showed that antenatal corticosteroid administration was associated with lower odds of neonatal mortality (aOR 0.59, 95% CI 0.43-0.80, I2 69%, five studies, 20,312 neonates) and RDS (aOR 0.70, 95% CI 0.57-0.86, I2 67%, seven studies, 20,628 neonates) in twins. Results were inconclusive for the other outcomes. CONCLUSION: Evidence from nonrandomized studies suggests antenatal corticosteroids are associated with lower incidence of neonatal mortality and RDS in twins. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42020205302.

Antenatal Corticosteroids to Asian Women Prior to Elective Cesarean Section at Early Term and Effects on Neonatal Respiratory Outcomes.

This exploratory study aimed to evaluate the effects of antenatal corticosteroids in singleton pregnancies of Asian women prior to elective cesarean section (CS) at early term on neonatal respiratory outcomes. METHODS: This is a pilot and pragmatic randomized trial conducted at a university hospital in Malaysia. Women with singleton pregnancies planned for elective CS between 37+0 and 38+6 weeks gestation were randomly allocated into the intervention group, where they received two doses of IM dexamethasone 12 mg of 12 h apart, 24 h prior to surgery OR into the standard care, control group, and both groups received the normal routine antenatal care. The primary outcome measures were neonatal respiratory illnesses, NICU admission and length of stay. RESULTS: A total of 189 patients were recruited, 93 women in the intervention group and 96 as controls. Between the steroid and control groups, the mean gestation at CS was similar, 266.1 ± 3.2 days (38 weeks) vs. 265.8 ± 4.0 days (37+6 weeks), p = 0.53. The mean birthweight of infants was 3.06 ± 0.41 kg vs. 3.04 ± 0.37 kg, p = 0.71. Infants with respiratory morbidities were primarily due to transient tachypnea of newborn (9.7% vs. 6.3%), and congenital pneumonia (1.1% vs. 3.1%) but none had respiratory distress syndrome. Only four infants required NICU admission (2.2% vs. 3.1%, p = 0.63). Their average length of stay was not statistically different; 3.5 ± 2.1 days vs. 5.7 ± 1.5 days, p = 0.27. CONCLUSIONS: Elective CS at early term before 39 weeks was associated with a modest overall incidence of neonatal respiratory illness (10.1%) in this Asian population. Antenatal dexamethasone did not diminish infants needing respiratory support, NICU admission and length of stay.

Premedication with Fentanyl for Less Invasive Surfactant Application (LISA): A Randomized Controlled Trial.

INTRODUCTION: Currently, there is no consensus regarding analgesic premedication before the surfactant administration by less invasive surfactant application (LISA) procedure. In this randomized controlled trial, we compared the level of comfort of preterm infants receiving fentanyl as analgesic and sedative versus no fentanyl during LISA procedure. METHODS: We randomized 34 preterm infants of 28+0-33+6 weeks of gestation with respiratory distress syndrome (RDS) within 6 h of birth to receive either fentanyl (1 µg/kg intravenous) or no premedication during surfactant administration by LISA procedure. Primary objective was to assess the proportion of preterm infants to be comfortable during the procedure [revised premature infant pain profile (R-PIPP) score ≤12] and secondarily complications occurring during the procedure, hemodynamically significant patent ductus arteriosus (hsPDA), intraventricular hemorrhage (IVH) (≥ grade 3), bronchopulmonary dysplasia (BPD) and composite outcome of BPD/mortality. RESULTS: Proportion of preterm infants with a R-PIPP score ≤12 during LISA was significantly higher in the fentanyl group [15/17 (88.23%) vs. 8/17 (47.05%); p value 0.025]. There were no differences in secondary outcome parameters. CONCLUSION: Low-dose fentanyl during LISA procedure resulted in more comfort in preterm infants and without increased complication of both the LISA procedure and fentanyl administration. Further studies are needed to determine the safest and most effective pharmacologic measures to prevent pain and discomfort during LISA.

Respiratory distress syndrome (RDS) in neonates is associated with prematurity, and surfactant administration is essential for its management. Surfactant instillation through a thin intratracheal catheter in spontaneously breathing infants with nasal continuous positive airway pressure (nCPAP) is known as less invasive surfactant application (LISA). Till date, there is no consensus regarding analgesic premedication before the surfactant administration by LISA procedure. In this randomized controlled trial, we compared the level of comfort of preterm infants receiving fentanyl as analgesic and sedative versus no fentanyl during LISA procedure. We reported that proportion of preterm infants with severe pain during LISA was significantly lower in the fentanyl group. There were no differences in clinical outcome parameters. So, we concluded that low-dose fentanyl during LISA procedure resulted in more comfort in preterm infants and without increased complication of both the LISA procedure and fentanyl administration.

Antenatal corticosteroids for women at risk of preterm delivery: the "Emperor's New Clothes" tale in medical practice.

OBJECTIVE: To introduce the effect of a single course of betamethasone for pregnant women at risk of preterm delivery (PTD). MATERIALS AND METHODS: In this study, a single course of 12 mg Bethamethasone was administered twice in 24 h (between 24-34 gestational weeks) for antenatal corticosteroid prophylaxis. Four hundred ninety-three neonates fulfilled the inclusion criteria and they were categorized (259 singletons, 192 twins and 42 triplets who met the inclusion criteria) into two groups according to the utilization of antenatal corticosteroid as control (n = 202) and study (n = 291) groups. We used respiratory distress syndrome (RDS), congenital pneumonia, intraventricular hemorrhage (IVH), neonatal sepsis, and bronchopulmonary dysplasia (BPD) as primary outcomes for the evaluation of neonatal morbidity. RESULTS: Study and control groups were similar in terms of clinical characteristics. RDS, congenital pneumonia, neonatal sepsis, and BPD rates were significantly higher in the study group (betamethasone) (p = .05, p = .007, 0.003, and 0.004, respectively) between 24-34 gestational weeks (when the neonates of multiple pregnancies were excluded from the analysis, we have demonstrated that congenital pneumonia (p = .033) and neonatal sepsis (p = .030) were still significantly higher in the betamethasone group). The neonates of 24-28 gestational weeks were compared separately and we demonstrated that RDS (p = .012), congenital pneumonia (p = .022), IVH (p = .044), neonatal sepsis (p = .023), and BPD (0.001) were also more frequent in the study group. When the 28-32 gestational week data were compared, IVH (p = .020) and neonatal sepsis (p = .017) were more frequent in the single course betamethasone users. However, we could not demonstrate a significant difference between the control and study groups between 32-34 gestational weeks in terms of the primary neonatal outcomes used in this study. CONCLUSION: Single course antenatal betamethasone administration may be ineffective on the respiratory complications of preterm and very preterm infants while it may be unfavorable for extremely preterm infants. WHAT IS NEW ABOUT THE PAPER, WHAT COULD ADD TO THE CURRENT KNOWLEDGE: Pregnant women at risk for preterm labor must be under intensive antenatal care programs, and if possible, necessary precautions must be undertaken to prevent fetal hypoxia together with etiology specific treatments. This approach might contribute to better perinatal outcomes than just administering antenatal corticosteroid therapy.

Rescue antenatal corticosteroids and neonatal outcomes in twin gestation.

OBJECTIVE: Although repeated antenatal corticosteroids (ACS) courses are not recommended, a single rescue ACS course has been shown to decrease neonatal morbidity among preterm singletons. However, little is known regarding the effects of rescue ACS course in twin pregnancies. METHODS: A retrospective cohort study conducted during 2015-2017 at a tertiary-care center including all twins delivered between 24-34 weeks of gestation who received at least one course of ACS. RESULTS: Overall, 162 (70.4%) twins were exposed to a single ACS course and 68 (29.6%) to an additional rescue ACS course. Rescue ACS course was associated with lower rates of respiratory distress syndrome (7.4% vs. 19.1%, p = .03), surfactant use (7.4% vs 18.5%, p = .04) and bronchopulmonary dysplasia (0 vs 8.6%, p = .01) as compared to a single ACS course. In the rescue ACS group, compared to the single ACS group, the rates of composite respiratory adverse outcome (10.3% vs 22.2%, OR [95% CI]: 0.40 (0.17-0.95), p = .04) and any adverse neonatal outcome (13.2% vs 26.5%, OR [95% CI]: 0.42 (0.19-0.92), p = .04) were significantly lower. Hospital stay was also shorter among neonates born to mothers receiving a rescue ACS course (median 23 vs. 30 days, p = .01). No differences were noted in neonatal birthweight, head circumference and the rate of neonatal hypoglycemia. CONCLUSION: Rescue ACS course was associated with improved respiratory and neonatal outcomes in twin gestations. Further studies are warranted to confirm our findings and better delineate the optimal regimen of rescue ACS in this setting.

Association of antenatal corticosteroids with morbidity and mortality among preterm multiple gestations: meta-analysis of observational studies.

OBJECTIVE: This meta-analysis aimed to assess the efficacy of antenatal corticosteroids (ACS) on morbidity and mortality among preterm multiple pregnancies. METHODS: The PubMed, Embase, Web of Science and Cochrane Library databases were searched for studies investigating the outcomes among preterm multiple gestations following to ACS, from their inception to 1 November 2020. Two authors independently performed the study selection, risk of bias assessment and data extraction. The primary outcomes were respiratory distress syndrome (RDS) and mortality and secondary outcomes included intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), necrotising enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia. Pooled ORs were obtained using random effects models. Subgroup analyses were performed to explain heterogeneity by ACS completeness, administration-to-delivery intervals (≤7 days) and single or multicentre. RESULTS: A total of 16 observational studies with 36 973 newborns were included in the meta-analysis. ACS treatment was associated with a reduction in RDS (OR 0.66; 95% CI 0.54 to 0.82; I2=91.4%; p<0.001), mortality (OR 0.64; 95% CI 0.50 to 0.81; I2=85.9%; p<0.001), IVH (OR 0.67; 95% CI 0.54 to 0.83; I2=77.4%; p<0.001) and PVL (OR 0.65; 95% CI 0.47 to 0.92; I2=75.5%; p<0.001). Subgroup analyses showed ACS completeness, administration-to-delivery interval and multicentre study affected these associations. DISCUSSION: ACS may be beneficial for reducing the risks of RDS, mortality, IVH and PVL among preterm multiple gestations. The efficacy of ACS could be affected by ACS completeness and administration-to-delivery. More robust evidence on the efficacy of ACS treatment among multiple gestations is warranted.

Can high-flow nasal cannula reduce the risk of bronchopulmonary dysplasia compared with CPAP in preterm infants? A systematic review and meta-analysis.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects the premature lung, and to reduce its incidence has been used non-invasive ventilatory support, such as continuous positive airway (CPAP) and high-flow nasal cannula (HFNC). Thus, the objective of this review was to assess whether the use of high flow nasal cannula (HFNC) compared to continuous positive airway pressure (CPAP) decreases the risk of bronchopulmonary dysplasia (BPD) in premature newborns. METHODS: The protocol was registered (Prospero: CRD42019136631) and the search was conducted in the MEDLINE, PEDro, Cochrane Library, CINAHL, Embase, and LILACS databases, and in the clinical trials registries, until July 2020. We included randomized clinical trials comparing HFNC versus CPAP use in premature infants born at less than 37 weeks of gestational age. The main outcome measures were the development of BPD, air leak syndrome, and nasal injury. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool and the GRADE system was used to summarize the evidence recommendations. Meta-analyses were performed using software R. RESULTS: No difference was found between HFNC or CPAP for the risk of BPD (RR: 1.10; 95% CI: 0.90-1.34), air leak syndrome (RR: 1.06; 95% CI: 0.52-2.14), and nasal trauma (RR: 2.00; 95% CI: 0.64-6.25), with a very low level of evidence. CONCLUSION(S): The HFNC showed similar results when compared to CPAP in relation to the risk of BPD, air leak syndrome, and nasal injury. In the literature, no randomized clinical trial has been found with BPD as the primary outcome to support possible outcomes.

ACE2 Promotes the Synthesis of Pulmonary Surfactant to Improve AT II Cell Injury via SIRT1/eNOS Pathway.

OBJECTIVE: We aimed to explore the level of PS, cell viability, inflammatory factors, and apoptosis in neonatal respiratory distress syndrome (ARDS). Besides, we explored the potential relationship between ACE2, SIRT1/eNOS pathway, and hypoxia-induced AT II cell damage. METHODS: The hUC-MSC-derived AT II cells were verified by IF and ICC, whereas qRT-PCR was used for PS and AT II cell marker (CK-8 and KGF). The AT II cell damage model was established by hypoxia exposure. The enhanced expression of ACE2 was tested after transfection with pcDNA3.1-ACE2 by western blot. The effects of hypoxia and ACE2 on AT II cells were evaluated by MTT, western blot, ELISA, and flow cytometry. The involvement of the SIRT1/eNOS pathway in AT II cell's protective functions against NRDS was verified with the addition of SIRT1 inhibitor EX527. RESULTS: Based on the successful differentiation of AT II cells from hUC-MSCs and the buildup of AT II cell damage model, the overexpressed ACE2 impeded the hypoxia-induced cellular damage of AT II cells. It also counteracted the inhibitory effects of hypoxia on the secretion of PS. Overexpression of ACE2 rescued the cell viability and suppressed the secretion of inflammatory cytokines and the apoptosis of AT II cells triggered by hypoxia. And ACE2 activated the SIRT1/eNOS pathway to play its cell-protective and anti-inflammatory roles. CONCLUSION: Our findings provided information that ACE2 prevented AT II cells from inflammatory damage through activating the SIRT1/eNOS pathway, which suggested that ACE2 might become a novel protective agent applied in the protection and treatment of NRDS.

Resveratrol as an anti-asthmatic agent: could this stilbenoid help against COVID-19 in any way? a meta-analysis / Resveratrol como agente antiasmático: ¿podría este estilbenoide ayudar contra el COVID-19 de alguna manera? un metaanálisis

Resveratrol is a phenolic phytoconstituent found in many plants. This molecule has always caught the attention of scientists because of biological potentials such as inhibition of inflammation, oxidative stress and platelet aggregation as well as to prevent/protect against cardiovascular and neurodegenerative disease/disorders. Literature search have been conducted over resveratrol in covid-19 and asthma studies published in Pubmed and Google Scholars until 30 September 2020. The criteria used in the literature review were determined and were reviewed works on resveratrol including 368 articles and 47 articles on covid-19 and asthma, respectively. As a result of meta-analysis, TNF-α values of the studies showed a significant difference (heterogeneity) of I2=68.39% from each other in total (Cohran Q:6.33, p<0.0423). This study shows that resveratrol would have a potential to reduce ARDS symptoms, by suppressing the cytokine storm and severe inflammation caused by SARS-CoV-2, and by showing strong activity against various types of DNA/RNA viruses.

El resveratrol es un fitoconstituyente fenólico que se encuentra en muchas plantas. Esta molécula siempre ha llamado la atención de los científicos debido a sus potenciales biológicos como la inhibición de la inflamación, el estrés oxidativo y la agregación plaquetaria, así como para prevenir/proteger contra enfermedades/trastornos cardiovasculares y neurodegenerativos. Se han realizado búsquedas bibliográficas sobre resveratrol en covid-19 y estudios sobre asma publicados en Pubmed y Google Scholars hasta el 30 de septiembre de 2020. Se determinaron los criterios utilizados en la revisión bibliográfica y se revisaron trabajos sobre resveratrol que incluyen 368 artículos y 47 artículos sobre covid-19 y asma, respectivamente. Como resultado del metanálisis, los valores de TNF-α de los estudios mostraron una diferencia significativa (heterogeneidad) de I2=68,39% entre sí en total (Cohran Q: 6,33, p<0,0423). Este estudio muestra que el resveratrol podría reducir los síntomas del ARDS al suprimir la tormenta de citocinas y la inflamación severa causada por el SARS-CoV-2, y al mostrar una fuerte actividad contra varios tipos de virus de ADN/ARN.

Is there a role for antenatal corticosteroids in term infants before elective cesarean section?

Abstract Objective Cesarean section (CS) delivery, especially without previous labor, is associated with worse neonatal respiratory outcomes. Some studies comparing neonatal outcomes between term infants exposed and not exposed to antenatal corticosteroids (ACS) before elective CS revealed that ACS appears to decrease the risk of respiratory distress syndrome (RDS), transient tachypnea of the neonate (TTN), admission to the neonatal intensive care unit (NICU), and the length of stay in the NICU. Methods The present retrospective cohort study aimed to compare neonatal outcomes in infants born trough term elective CS exposed and not exposed to ACS. Outcomes included neonatal morbidity at birth, neonatal respiratory morbidity, and general neonatal morbidity. Maternal demographic characteristics and obstetric data were analyzed as possible confounders. Results A total of 334 newborns met the inclusion criteria. One third of the population study (n=129; 38.6%) received ACS. The present study found that the likelihood for RDS (odds ratio [OR]=1.250; 95% confidence interval [CI]: 0.454-3.442), transient TTN (OR=1.,623; 95%CI: 0.556-4.739), and NIUC admission (OR=2.155; 95%CI: 0.474-9.788) was higher in the ACS exposed group, although with no statistical significance. When adjusting for gestational age and arterial hypertension, the likelihood for RDS (OR=0,732; 95%CI: 0.240-2.232), TTN (OR=0.959; 95%CI: 0.297--3.091), and NIUC admission (OR=0,852; 95%CI: 0.161-4.520) become lower in the ACS exposed group. Conclusion Our findings highlight the known association between CS-related respiratory morbidity and gestational age, supporting recent guidelines that advocate postponing elective CSs until 39 weeks of gestational age.

Does surfactant nebulization prevent early intubation in preterm infants? A protocol for a systematic review and meta-analysis.

BACKGROUND: Respiratory distress syndrome (RDS) is the most common cause of respiratory failure in preterm infants. Treatment consists of respiratory support and exogenous surfactant administration. Commonly, surfactant is administered intratracheally. However, this requires airway instrumentation and subsequent fluid instillation which may be harmful. Surfactant nebulization (SN) may offer a safe and effective alternative for surfactant administration, but the clinical efficacy is not yet established. Thus, this systematic review and meta-analysis of randomized controlled trials will summarize the available evidence to determine the effectiveness and safety of SN for the prevention of intubation and subsequent mechanical ventilation at 72 h after birth. METHODS: A systematic literature search in Medline, Embase, and The Cochrane Library will be performed, and all randomized controlled trials (RCTs) and quasi-RCTs from published articles, presentations, and trial registries will be included in this meta-analysis. Titles and abstracts of all records identified in the search will be screened by two reviewers independently. Data on preterm infants (≤ 37 weeks) receiving nebulized surfactant in the first 72 h after birth for the treatment or prevention of RDS will be evaluated. Primary outcome is the intubation rate by 72 h after birth, and secondary outcomes include peridosing safety effects as well as major neonatal morbidities. Risk of bias will be assessed using the revised Cochrane ROB tool, and subgroup analyses will be performed to evaluate potential confounding factors. Publication bias will be assessed by examining a funnel plot. The meta-analysis will be performed using a fixed-effects model. DISCUSSION: This review will provide an evidence-based tool for information about surfactant nebulization, illustrating the current knowledge and hopefully revealing potential novel avenues for researchers and clinicians alike. SYSTEMATIC REVIEW REGISTRATION: This review is registered with the publicly available resource PROSPERO ( CRD42020175625 ).