Male fetuses often prioritise fetal growth over placental reserve, potentially compromising feto-placental adaptability and heightening vulnerability to in-utero stress and adverse outcomes, including fetal growth restriction (FGR) and stillbirth. However, the physiological drivers underlying this vulnerability remain unclear. Employing in-silico models, we investigated how sex-specific placental vascular anatomy influences haemodynamics and contributes to FGR pathophysiology.
Multiscale anatomical data was collected from normal (male n=20, female n=20) and FGR (male n=9, female n=3) placentae, including chorionic plate arterial branching metrics, and stereological vascular density. Personalised geometric models were iteratively generated from patients' anatomical data. Blood flow simulations were performed for each patient geometry to understand the sex-specific impact of vascular structure on haemodynamics.
Anatomical data reveal male FGR placentae exhibited longer, thinner chorionic plate arteries (p≤0.002). Normal male placentae demonstrated reduced vascularity compared to females (p≤0.046), with no sex-differences in FGR (p≥0.991). Stereological vascular density of each cohort was matched by scaling intermediate villous branch number in the personalised models. The level of branching was consistent across normal male, female and FGR male cohorts, with branching in the female FGR cohort being 2.78-fold lower. Modelled vascular volumes matched stereology (p≥0.7179), confirming accurate sex-specific anatomy. Female FGR placentae required 50% lower increase in branching density adjustment to align modelled vessel density with stereology. Flow simulations predicted higher umbilical artery driving pressure in male FGR than normal male placentae (7410 vs 4542 pa, p>0.045).
Sex-specific vascular perturbations in FGR suggest divergent mechanisms of placental maladaptation with different functional consequence. Female FGR placentae demonstrated reduced vascular branching in the villous tissue. Whereas male FGR placentae exhibited higher order vascular maldevelopment characterised by elongated, reduced-calibre chorionic plate arteries. The male FGR phenotype was predicted to have a greater haemodynamic impact, which may contribute to the increased susceptibility of male fetuses to adverse outcomes.