The association between collagenopathies and the risk of spontaneous preterm birth: A systematic review with selective meta-analysis.

Abstract

Introduction: Spontaneous preterm birth (sPTB) remains a leading cause of neonatal morbidity and mortality. Inherited collagenopathies, including Ehlers-Danlos syndrome (EDS) and Marfan syndrome (MFS), may predispose to sPTB through impaired connective tissue integrity; however, the available evidence has not been systematically synthesized according to collagenopathy subtype. We aimed to evaluate the association between inherited collagenopathies and sPTB through a systematic review, undertaking quantitative synthesis only where clinically appropriate and methodologically comparable.

Material and methods: This systematic review followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251021631). MEDLINE (PubMed), Embase (Ovid), Scopus, Web of Science, and the Cochrane Library were searched from inception to 30 April 2025. Observational studies comparing pregnancy outcomes in women with inherited collagenopathies and women without collagenopathies were eligible. The primary outcome was sPTB before 37 weeks' gestation. Findings were synthesized narratively according to collagenopathy subtype. Meta-analysis using a Mantel-Haenszel fixed-effect model was undertaken only for clinically comparable MFS studies.

Results: Fourteen observational studies met the inclusion criteria. Four studies evaluated MFS, seven evaluated EDS, one assessed vascular EDS exclusively and two included mixed collagenopathy cohorts. Meta-analysis demonstrated that women with MFS had significantly higher odds of sPTB than controls (OR 2.71, 95% CI 2.23-3.30; p < 0.001; I² = 41%). Studies of EDS demonstrated substantial clinical and methodological heterogeneity, precluding meaningful primary quantitative synthesis. Nevertheless, narrative synthesis consistently identified increased frequencies of sPTB and obstetric complications.

Conclusions: Inherited collagenopathies appear to be associated with an increased risk of sPTB, although the certainty of evidence differs across phenotypes. The strongest comparative evidence currently exists for MFS, whereas evidence for EDS syndrome remains limited by substantial clinical heterogeneity. These findings support phenotype-specific obstetric assessment and highlight the need for prospective studies with standardized subtype classification and outcome reporting.