Antenatal Sildenafil for Congenital Diaphragmatic Hernia: A Systematic Review and Bayesian Meta-Analysis of Preclinical Studies.

Background: In congenital diaphragmatic hernia (CDH), pulmonary hypoplasia and pulmonary hypertension are major causes of morbidity and mortality. Antenatal treatment with sildenafil has shown some promising protective effects in experimental CDH, but no systematic review has yet evaluated the preclinical evidence on this topic. Methods: PubMed and EMBASE databases were searched for studies using antenatal sildenafil in animal models of CDH. Bayesian model-averaged (BMA) meta-analysis was used to calculate Bayes factors (BFs). The BF₁₀ is the ratio of the probability of the data under the alternative hypothesis (presence of effect) over the probability of the data under the null hypothesis (absence of effect). Risk of bias was assessed by the SYRCLE tool. Results: We included 18 studies (14 nitrofen and 4 surgical CDH). The BMA analysis showed inconclusive evidence (BF₁₀ between 0.33 and 3) for the presence of an effect of sildenafil in fetal survival (7 studies, BF₁₀ = 1.25) or in lung hypoplasia as assessed by the lung-to-body weight ratio (16 studies, BF₁₀ = 2.04). In contrast, the BMA analysis showed conclusive evidence (BF₁₀ > 3) in favor of a positive effect of sildenafil on small pulmonary arteries medial wall thickness (12 studies, BF₁₀ = 1499), radial alveolar count (6 studies, BF₁₀ = 167.57), interalveolar septa thickness (4 studies, BF₁₀ = 56.86), distal airway complexity (3 studies, BF₁₀ = 7.95), mean saccular airspace diameter (2 studies, BF₁₀ = 7.61), total lung capacity (2 studies, BF₁₀ = 6.91), lung compliance (2 studies, BF₁₀ = 5.19), and VEGF expression (5 studies, BF₁₀ = 10.62). Conclusions: In preclinical models of CDH, antenatal sildenafil rescues pulmonary vascular remodeling and airway/airspace morphometric alterations.