Academic Background

The placenta plays a critical role in health and disease during pregnancy, and its development and function directly impact pregnancy outcomes. The early development of the utero-placental vasculature is essential for ensuring normal placental function, while abnormal vascular development is closely associated with placenta-related complications such as fetal growth restriction, preeclampsia, and preterm birth. To ensure adequate development of the utero-placental vasculature, the maternal uterine vessels undergo a series of adaptive changes, including the formation, dilation, and funneling of spiral arteries. Therefore, markers that monitor the development of the utero-placental vasculature in early pregnancy can provide unique insights into the pathophysiology of placental development and related complications.

The placenta produces various pro-angiogenic and anti-angiogenic factors that influence maternal vascular adaptation to pregnancy, including placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng). PlGF stimulates vasodilation and angiogenesis in the utero-placental and feto-placental circulations by binding to the vascular endothelial growth factor receptor-1 (VEGFR-1). sFlt-1, a soluble variant of VEGFR-1, binds to circulating PlGF, thereby inhibiting its bioavailability and pro-angiogenic functions. sEng exerts anti-angiogenic effects by binding and neutralizing free transforming growth factor beta (TGFβ). The circulating levels of these angiogenic factors are directly related to vascular development, and their imbalance in the second and third trimesters plays a crucial role in the pathogenesis of preeclampsia. However, the relationship between circulating angiogenic factors and the development of the utero-placental vasculature in early pregnancy remains incompletely understood.

Research Background and Objectives

This study aimed to investigate the associations between maternal serum angiogenic factors (PlGF, sFlt-1, and sEng) and the development of the utero-placental vascular volume (UPVV) and vascular skeleton (UPVS) in early pregnancy. UPVV and UVPS are novel imaging markers generated using three-dimensional (3D) power Doppler ultrasound, virtual reality (VR), and skeletonization algorithms, reflecting the volumetric and morphological (branching) development of the utero-placental vasculature, respectively. The study hypothesized that higher levels of PlGF, lower levels of sFlt-1 and sEng, or lower sFlt-1/PlGF and sEng/PlGF ratios are associated with increased development of the utero-placental vasculature in early pregnancy.

Research Methods

This study was based on a subcohort of the ongoing Rotterdam Periconception Cohort, known as the Virtual Placenta Study, and included 185 women with ongoing pregnancies. Placental images were obtained using 3D power Doppler ultrasound at 7-11 weeks of gestation, and UPVV and UVPS were measured. UPVV, as a parameter of volumetric development, was reported in cm³, while UVPS, as a parameter of morphological development, reported the number of endpoints, bifurcation points, crossing points, or vessel points, as well as the total vascular length. Maternal serum biomarkers, including PlGF, sFlt-1, and sEng, were assessed at 11 weeks of gestation, and the sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression analysis was used to estimate the associations between serum biomarkers and the trajectories of UPVV and UVPS development.

Research Results

The results showed that maternal serum PlGF levels were positively associated with the development of UPVV and UVPS (UPVV: β = 0.39, 95% CI = 0.15;0.64; bifurcation points: β = 4.64, 95% CI = 0.04;9.25; crossing points: β = 4.01, 95% CI = 0.65;7.37; total vascular length: β = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). The sEng/PlGF ratio was negatively associated with the development of UPVV and UVPS. No associations were observed between sFlt-1, sEng, or the sFlt-1/PlGF ratio and the development of UPVV and UVPS.

Conclusion

The study concluded that increased maternal serum PlGF concentrations in early pregnancy are associated with enhanced development of the utero-placental vasculature, as reflected by UPVV and UVPS measurements. This finding provides new insights into the early prediction of placenta-related complications and supports the application of PlGF in early prediction models. In contrast, sFlt-1 and sEng appear to have a limited influence on the development of the utero-placental vasculature in early pregnancy, thus their added value in the early detection of placenta-related complications is likely to be minimal.

Research Highlights

1. Novel Imaging Markers: This study is the first to use UPVV and UVPS as 3D power Doppler imaging markers to monitor the volumetric and morphological development of the utero-placental vasculature in early pregnancy.
2. Key Role of PlGF: The study confirmed the critical role of PlGF in the development of the utero-placental vasculature in early pregnancy, providing new mechanistic insights into the early prediction of placenta-related complications.
3. Potential for Clinical Application: The measurements of UPVV and UVPS offer new tools for studying early vascular development, improving our understanding of the pathophysiology of placenta-related complications, and informing preventive treatments such as aspirin administration.

Research Significance

This study provides new imaging markers for monitoring the development of the utero-placental vasculature in early pregnancy and highlights the key role of PlGF in this process. These findings not only enhance our understanding of the pathophysiology of placenta-related complications but also offer new avenues for early prediction and intervention. In the future, the measurements of UPVV and UVPS are expected to be widely applied in clinical research, particularly in the early prediction and prevention of placenta-related complications such as preeclampsia.

Authors and Institutions

This study was conducted by Eline S. de Vos, A. H. Jan Danser, Anton H. J. Koning, Sten P. Willemsen, Lotte E. van der Meeren, Eric A. P. Steegers, Régine P. M. Steegers-Theunissen, and Annemarie G. M. G. J. Mulders, affiliated with the Departments of Obstetrics and Gynecology, Pharmacology, Pathology, and Biostatistics at Erasmus University Medical Center in Rotterdam, the Netherlands. The study was published online on August 14, 2024, in the journal Angiogenesis.