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Antenatal Sildenafil for Congenital Diaphragmatic Hernia: A Systematic Review and Bayesian Meta-Analysis of
Tamara M Hundscheid1, Ilaria Amodeo2, Giacomo Cavallaro3
1Division of Neonatology, Department of Pediatrics, MosaKids Children's Hospital, Maastricht University Medical Center (MUMC+), Research Institute for Oncology and Reproduction (GROW), Maastricht University, 6202 AZ Maastricht, The Netherlands.
Insights
Antenatal sildenafil shows promise for congenital diaphragmatic hernia (CDH) treatment. Preclinical studies indicate it improves lung development and vascular remodeling in CDH models, though effects on fetal survival and overall lung hypoplasia remain inconclusive.
Area of Science:
- Neonatal Medicine
- Developmental Biology
- Pharmacology
Background:
- Congenital diaphragmatic hernia (CDH) is a severe condition characterized by pulmonary hypoplasia and hypertension, leading to significant morbidity and mortality.
- Antenatal sildenafil has demonstrated potential protective effects in experimental CDH models.
- A systematic review of preclinical evidence on antenatal sildenafil for CDH is lacking.
Purpose of the Study:
- To systematically evaluate the preclinical evidence on the efficacy of antenatal sildenafil in animal models of congenital diaphragmatic hernia.
- To assess the impact of antenatal sildenafil on fetal survival, lung hypoplasia, and specific lung morphometric parameters in CDH models.
Main Methods:
- A comprehensive search of PubMed and EMBASE databases was conducted for studies investigating antenatal sildenafil in CDH animal models.
- Bayesian model-averaged (BMA) meta-analysis was employed to calculate Bayes factors (BFs) for assessing evidence strength.
- Risk of bias was evaluated using the SYRCLE tool.
Main Results:
- The meta-analysis included 18 studies (14 nitrofen-induced and 4 surgical CDH models).
- Evidence for sildenafil's effect on fetal survival (BF10 = 1.25) and lung-to-body weight ratio (BF10 = 2.04) was inconclusive.
- Conclusive evidence (BF10 > 3) supported a positive effect of antenatal sildenafil on pulmonary artery wall thickness, alveolar count, airway complexity, lung capacity, compliance, and VEGF expression.
Conclusions:
- In preclinical CDH models, antenatal sildenafil effectively rescues pulmonary vascular remodeling.
- Antenatal sildenafil also ameliorates airway and airspace morphometric alterations in CDH models.
- Further research may explore the clinical translation of these findings.
Abstract:
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.
