PM1047: Evaluating Preterm Birth as a Biomarker of Major Events in Children with Vascular Ehlers-danlos Syndrome

Background: Vascular Ehlers-Danlos syndrome (VEDS) is a rare, hereditary connective tissue disorder conferring high risk of spontaneous arterial dissection, rupture, and hollow organ rupture. Children with VEDS are more likely to be born prematurely, which is suspected to be secondary to increased amniotic sac fragility. We hypothesized that the degree of sac fragility, as measured by gestational age (GA) at birth, would be associated with severity of the VEDS presentation, as demonstrated by occurrence and timing of major events.

Methods: This was a retrospective cohort study including subjects with a pathogenic or likely pathogenic COL3A1 variant and clinical diagnosis of VEDS. Preterm birth was defined as GA at birth < 37 weeks. The primary outcome was major event before the age of 18 years, defined as arterial dissection, rupture, hollow organ rupture, or pneumothorax. Analysis was performed by risk-stratified genotype, classifying missense/splice site as high-risk, and null/deletion as low-risk. This was performed to control for potential confounding or effect modification by variant type. Cox proportional hazards regression and log-rank test were used to assess the association between preterm birth and event.

Results: Forty patients were included (70% male), of which 50% were born preterm (55% of high-risk and 17% of low-risk). Eighty-three percent (33/40) had a high-risk variant (17 missense, 16 splice site variants). One individual with an intronic mutation was excluded from risk-stratified analysis. Median age at follow-up was 12.2 years (IQR 6.9y, 15y). Eight patients (20%) had an event, including 3 aortic/arterial events (1 peri-operative aortic rupture in 10y male and 2 left internal carotid dissections in monozygotic male twins at ages 10y and 12y). Other events included 3 bowel ruptures (all females, 4y, 14y, and 16y), 1 intraperitoneal bladder rupture (male, 4y), and 1 pneumothorax (male, 16y). When limiting to the high-risk cohort, 28% (5/18) of those born preterm had an event in childhood compared to 13% (2/15) of those born full-term (HR 2.5, 95% 0.5-12.7, p=0.29). Among the low-risk cohort, the only patient born preterm also had an event (100%) while no one born at term (0/5) had an event (0%) (log-rank p=0.01). Among those with high-risk variants, when limiting the outcome to aortic/arterial events, 17% (3/18) of those born preterm had an event, compared to 0% (0/15) of those born at term (log-rank p=0.10).

Conclusion: Children with VEDS and preterm birth in this cohort had a greater hazard for a major event, even when stratified by variant risk, although this did not meet statistical significance. Although this study’s statistical power was limited, these findings suggest preterm birth may aid in risk stratification. Additional studies with improved sample size are warranted.