Daily Respiratory Research Analysis
A multicenter randomized trial showed that antenatal betamethasone in twin pregnancies at risk of late preterm delivery reduced severe neonatal respiratory morbidity but increased neonatal hypoglycemia, with benefits concentrated when birth occurred 12 hours to <7 days after dosing. Mechanistic work revealed human CD4 T cells as direct targets for lipid nanoparticle mRNA vaccines, refining our understanding of vaccine-induced immunity. Longitudinal data showed accelerated FVC decline beginning f
Summary
A multicenter randomized trial showed that antenatal betamethasone in twin pregnancies at risk of late preterm delivery reduced severe neonatal respiratory morbidity but increased neonatal hypoglycemia, with benefits concentrated when birth occurred 12 hours to <7 days after dosing. Mechanistic work revealed human CD4 T cells as direct targets for lipid nanoparticle mRNA vaccines, refining our understanding of vaccine-induced immunity. Longitudinal data showed accelerated FVC decline beginning five years before menopause, underscoring sex-specific trajectories of lung aging.
Research Themes
- Perinatal prevention of respiratory morbidity
- Vaccine immunology and lipid nanoparticle delivery mechanisms
- Sex-specific trajectories in pulmonary aging
Selected Articles
1. Antenatal Corticosteroid in Twin-Pregnant Women at Risk of Late Preterm Delivery: A Randomized Clinical Trial.
In 812 twin pregnancies at 34–36+5 weeks, antenatal betamethasone reduced severe neonatal respiratory morbidity (RR 0.64) and decreased CPAP ≥2 h use and transient tachypnea, with no perinatal deaths in either arm. Benefits were time-dependent (delivery 12 h to <7 days after dosing), while neonatal hypoglycemia was more frequent in the steroid group.
Impact: This is the first adequately powered randomized, placebo-controlled trial demonstrating respiratory benefit of antenatal steroids specifically in twin late preterm pregnancies, addressing a key evidence gap with immediate translational relevance.
Clinical Implications: For twin pregnancies at risk of late preterm birth, consider antenatal betamethasone to reduce neonatal respiratory morbidity, optimizing timing so delivery occurs 12 hours to <7 days after the first dose; implement glucose monitoring protocols to manage increased neonatal hypoglycemia.
Key Findings
- Severe neonatal respiratory morbidity: 4.8% with betamethasone vs 7.5% with placebo (RR 0.64, 95% CI 0.42–0.98).
- Lower CPAP use ≥2 h (RR 0.58, 95% CI 0.35–0.95) and lower transient tachypnea of the newborn (RR 0.47, 95% CI 0.25–0.89).
- Efficacy observed only when delivery occurred 12 h to <7 days after the first dose.
- Neonatal hypoglycemia increased with betamethasone (15.6% vs 11.7%; RR 1.33, 95% CI 1.01–1.75).
- No perinatal deaths; no difference in neonatal sepsis or maternal chorioamnionitis.
Methodological Strengths
- Multicenter, randomized, placebo-controlled design with intention-to-treat analysis.
- Prospectively defined primary endpoint and trial registration (NCT03547791).
Limitations
- Conducted in a single country (Korea), which may limit generalizability.
- Not powered to assess rare adverse outcomes; benefit was time-window dependent.
Future Directions: Replicate findings across diverse populations, refine optimal dosing-to-delivery timing strategies in twins, and evaluate metabolic mitigation protocols to reduce hypoglycemia risk.
IMPORTANCE: Recent guidelines have recommended corticosteroid injection in women with singleton pregnancies at risk of late preterm delivery. However, the effectiveness of antenatal corticosteroid administration in women with twin pregnancies at risk of late preterm delivery has not been evaluated, and studies on this population are lacking. OBJECTIVE: To evaluate whether antenatal betamethasone administration reduces the risk of neonatal respiratory morbidity in late preterm twin neonates. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter randomized trial, twin-pregnant women at 34 weeks 0 days to 36 weeks 5 days of gestation at risk of late preterm delivery were enrolled across 8 university-based clinical centers in Korea. Data were collected between May 2018 and July 2024. Intention-to-treat analysis was performed. INTERVENTION: The participants received 2 injections of betamethasone or placebo after randomization (1:1). MAIN OUTCOMES AND MEASURES: The primary outcome was perinatal death within 72 hours after birth or severe neonatal respiratory morbidity. The exploratory outcomes were mild neonatal respiratory morbidities, other neonatal respiratory morbidities, other neonatal complications, or maternal complications. RESULTS: A total of 812 participants were randomized and analyzed, with 410 in the intervention group (median [IQR] age, 35 [33-37] years) and 402 in the placebo group (median [IQR] age, 35 [32-38] years). Among 1620 neonates (818 in the intervention group and 802 in the placebo group), there were no perinatal deaths in either group, and severe neonatal respiratory morbidity occurred in 99 neonates (6.1%), with lower risk in the betamethasone group than in the placebo group (39 [4.8%] vs 60 [7.5%]; relative risk [RR], 0.64 [95% CI, 0.42-0.98]). For the exploratory outcomes, continuous positive airway pressure use for 2 hours or more (RR, 0.58 [95% CI, 0.35-0.95]) and transient tachypnea of the newborn (RR, 0.47 [95% CI, 0.25-0.89]) were lower in the betamethasone group. The risk of primary outcome and mild respiratory morbidities was reduced only in neonates delivered between 12 hours or more and less than 7 days after the first betamethasone administration. The risk of neonatal hypoglycemia was increased in the betamethasone group (128 [15.6%] vs 94 [11.7%]; RR, 1.33 [95% CI, 1.01-1.75]), but the risk of neonatal sepsis or maternal chorioamnionitis did not differ between the 2 groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, antenatal betamethasone administration in women with twin pregnancies at risk of late preterm delivery significantly reduced the risk of neonatal respiratory morbidity. The outcomes from this study could serve as a valuable reference in clinical management of twin pregnancies at risk of late preterm delivery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03547791.
2. Human CD4 T cells are a functional target for lipid nanoparticle-based mRNA vaccines.
Using fluorescent reporter mRNA-LNPs and human immune samples, the authors demonstrate that CD4 T cells are a direct and functional target for LNP-mediated protein expression, challenging assumptions that antigen expression is confined mainly to myeloid or stromal cells. These findings refine the cellular map of mRNA vaccine action and have implications for optimizing vaccine formulations and dosing.
Impact: Identifying CD4 T cells as expression targets reorients mechanistic models of mRNA vaccine priming and may influence adjuvantation, LNP chemistry, and dosing strategies to optimize helper T cell responses.
Clinical Implications: While preclinical/mechanistic, the data suggest vaccine formulations could be tuned to enhance CD4 T cell priming, potentially improving breadth, durability, and quality of immune responses (e.g., Th1 polarization) for respiratory pathogens.
Key Findings
- CD4 T cells are a functional target for LNP-mediated protein expression as shown by fluorescent reporter mRNA-LNPs.
- Findings challenge prior assumptions limiting in vivo antigen expression mainly to myeloid/stromal compartments.
- Results provide a mechanistic basis to optimize mRNA vaccine design for improved helper T cell responses.
Methodological Strengths
- Direct cell-targeting assessment using fluorescent reporter mRNA-LNPs.
- Use of primary human immune samples to enhance translational relevance.
Limitations
- Preclinical/mechanistic study without clinical efficacy endpoints.
- Incomplete characterization of tissue distribution and durability of expression.
Future Directions: Define the kinetics, tissue distribution, and functional consequences of CD4-targeted expression in vivo; evaluate how LNP composition and dosing modulate helper T cell quality and vaccine efficacy.
Billions of mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lipid nanoparticle (LNP) vaccine doses have been administered globally and shown to be both safe and effective. However, the mechanisms by which mRNA vaccines facilitate protection remain unclear. Peripheral blood analyses from vaccinated individuals show B and T cell responses are elicited, but it remains unknown which cells contribute to particle uptake and protein expression to elicit protective immunity. Using mRNA LNP fluorescent reporters, we show that CD4 T cells are an unexpected target for LNP-based protein expression
3. Lung Function Changes Across the Menopausal Transition: A Longitudinal Analysis of Annual Examinations.
In a cohort of 5,554 women with 53,110 visits (median follow-up 11 years), the rate of FVC decline accelerated beginning five years before menopause and remained faster thereafter, while FEV1 did not show a similar acceleration. Findings highlight a sex-specific pattern of midlife lung aging linked to menopausal transition.
Impact: This large longitudinal analysis provides robust evidence that menopausal transition independently associates with accelerated restrictive physiology (FVC decline), informing timing for risk assessment and prevention strategies in women.
Clinical Implications: For midlife women, clinicians should consider menopausal status when interpreting spirometry, anticipate potential FVC decline acceleration, and reinforce preventive measures (e.g., physical activity, weight management, air pollution mitigation) and timing of longitudinal monitoring.
Key Findings
- Among 5,554 women (53,110 visits), the rate of FVC decline accelerated starting 5 years before menopause and persisted thereafter.
- FEV1 did not exhibit a similar acceleration in decline across the menopausal transition.
- Menopausal status, defined by a data-driven method, was independently associated with lung function trajectories in midlife.
Methodological Strengths
- Large sample with long median follow-up and repeated annual measures.
- Data-driven menopausal classification and exclusion of participants with respiratory disease.
Limitations
- Menopausal status was self-reported, potentially introducing misclassification.
- Single-country healthcare setting may limit global generalizability.
Future Directions: Clarify mechanisms linking hormonal changes to restrictive physiology, assess modifiable factors that buffer FVC decline, and evaluate whether targeted interventions around menopausal transition alter long-term pulmonary outcomes.
BACKGROUND: Trajectories of pulmonary function across the menopausal transition remain poorly understood. RESEARCH QUESTION: How do trajectories of FVC and FEV STUDY DESIGN AND METHODS: In this retrospective cohort study, we analyzed women in the St. Luke's Health Check-up Database (2004-2020) with ≥ 1 examination before and after self-reported menopause and with no respiratory disease. Menopausal status was classified into premenopause, perimenopause, or postmenopause using a data-driven method. Outcomes included FVC and FEV RESULTS: We included 5,554 women (53,110 visits; median age at menopause, 52 years [interquartile range (IQR), 50-54 years]). Median follow-up was 11.0 years (IQR, 7.0-14.1 years) with a median of 10 visits (IQR, 6-14 years). Median FVC and FEV INTERPRETATION: The rate of FVC decline increased 5 years before menopause and persisted at an increased rate of decline thereafter, suggesting that menopausal status is associated with lung function trajectories in midlife women, whereas FEV