Placenta: formation and development

The embryo's first contact with the maternal mucosa occurs at the blastocyst stage: the trophoblastic membrane begins to invaginate into the deciduous mucosa, forming the primary rudiments of the future placenta and chorionic sac. This process requires coordinated communication between the embryonic trophoblasts and the maternal endometrium. [1]

The first trophoblastic cells divide into two main groups: the cytotrophoblast and the syncytiotrophoblast. The syncytiotrophoblast rapidly expands, penetrating the decidual tissue, while the cytotrophoblast serves as a source for further placental cell differentiation and villus formation. These events occur within days and weeks after implantation. [2]

In parallel, primary villi—protrusions of the trophoblast—form, which then develop into the complex structure of chorionic villi and the fetal vascular network. In the very early stages, the placenta does not yet have mature vascular connections and is largely dependent on utero-desidual sources of nutrition. [3]

The surrounding maternal immune landscape is actively restructured: local immune cells of the decidual tissue interact with trophoblasts, ensuring tolerance to the fetal genome while simultaneously controlling invasion. Disruptions in this early coordination are associated with early pregnancy loss and placental echnogenic malformations. [4]

Table 1. Early morphological stages

Stage	Key events	Clinical significance
Blastocyst	Attachment to the endometrium	A permeable decidual environment is required. [5]
Syncytiotrophoblast	Implantation into the uterus	Formation of the placental "leg". [6]
Primary villi	Beginning of villous growth	Prerequisite for vascular development. [7]
Decidual reactions	Immune adaptation	The key to tolerance and control of infestation. [8]

Trophoblast differentiation and villus formation

The cytotrophoblast gives rise to two important populations: villous trophoblasts, which form the placental structure proper, and extravillous trophoblasts, which migrate into the uterine wall and vessels. These trophoblast types have different phenotypes and functions. [9]

The villous trophoblast organizes into placental villi, within which the fetal vascular network develops; the syncytial layer above them provides a barrier and active transport of substances. Extravillous trophoblasts mediate the invasion and remodeling of the uterine spiral arteries. [10]

Key markers and signaling pathways control trophoblast differentiation: Wnt, Notch, TGF-β, and vascular growth factors. Their precise temporal activity determines the balance between adequate invasion and its suppression, which is crucial for normal placental development. [11]

In recent years, experimental models using human trophoblast organoids and stem cell systems have provided unique mechanistic insights into how the matrix and microenvironment direct trophoblast fate and opened avenues for laboratory replication of the early stages of placentation. These models help understand the causes of pathology in humans. [12]

Table 2. Types of trophoblast and their functions

Trophoblast type	Localization	Function	Markers/paths
Syncytiotrophoblast	Surface of the villi	Barrier, secretion of hormones	hCG, protein synthesis; Wnt regulation. [13]
Cytotrophoblast	Inside the villi	Syncytium repopulation	Cellular proliferative reserve. [14]
Extravillous trophoblast	Invasive zone	Arterial remodeling	Invasion, Notch and TGF-β regulation. [15]

Formation of uteroplacental circulation and arterial remodeling

A key event in early placentation is the transformation of the uterine spiral arteries into low-resistance vessels: extravillous trophoblasts invade the vascular wall and replace the endothelium and smooth muscle elements, creating a constant high blood flow to the placenta. This remodeling ensures the sustained perfusion necessary for fetal growth. [16]

Insufficient invasion and incomplete remodeling of spiral arteries are associated with complications such as preeclampsia and intrauterine growth restriction. Current genetic and epigenetic understanding points to a complex interaction between maternal tissue, trophoblasts, and the immune environment during this process. [17]

Functionally, the formation of uteroplacental blood flow occurs in waves: the early stages are characterized by periods of low oxygen perfusion, which regulates further trophoblast differentiation; then, as vessels remodel, oxygen saturation increases and changes the expression of key genes. [18]

New spatially resolved tissue transcriptomics studies have revealed the migration chronology and molecular dynamics of precisely those EVT populations involved in remodeling, identifying potential targets for the early diagnosis of remodeling disorders. These findings are gradually being translated into clinical applications. [19]

Table 3. Uteroplacental remodeling: stages and consequences

Stage	What's happening	Possible consequences in case of violation
Early EVT invasion	Vascular endothelial replacement	Preeclampsia, FGR. [20]
Expansion of the lumen	Increased uterine blood flow	Adequate fetal perfusion
Stabilization	Setting low resistance	Supporting fetal growth
Failure	Chronic placental hypoperfusion	Hypoxia, maternal vascular complications. [21]

Growth, branching of villi and development of the vascular network of the placenta

After the first weeks of development, a phase of active branching of the villi and the formation of the fetal arteriovenous network within the placenta begins. Fetal vessels penetrate the villi, forming an exchange surface where diffusion and active transport ensure fetomaternal exchange. [22]

Vascular growth is regulated by angiogenesis factors such as VEGF, PLGF, and their receptors. The balance of pro- and anti-angiogenic factors in the placenta and maternal circulation reflects placental health and correlates with the risk of preeclampsia. Changes in these signals are now used in biomarkers of complication risk. [23]

Villus architecture takes its final form in the third trimester: terminating villi develop, providing a thin barrier for efficient gas exchange and extensive capillary network. Placental mass and villus area correlate with fetal weight and future postnatal health. [24]

The dynamics of vascular network formation are sensitive to maternal conditions: hypoxia, nutrient deficiency, and inflammation alter angiogenesis and lead to persistent structural changes that can impact the long-term health of the child. This is one of the mechanisms by which diseases are programmed later in life. [25]

Molecular Regulation: Key Pathways and Epigenetics

Placental development is controlled by a complex set of signaling cascades: Wnt and Notch regulate trophoblast fate, TGF-β and metalloproteinases regulate migration and remodeling, and VEGF regulates angiogenesis. Disruption of these pathways alters invasion, vascular organization, and placental transport function. [26]

Epigenetic mechanisms, including DNA methylation and microRNA regulation, determine network changes in gene expression in trophoblasts and decidual tissue. These levels of regulation explain why identical genetic variants sometimes lead to different clinical presentations depending on the environment. [27]

Current research areas include the study of super-enhancers, ubiquitin-linked regulation, and spatial transcriptomics of placental tissue. These approaches are identifying new target molecules and providing mechanistic explanations for clinical phenomena such as preeclampsia and fetal growth restriction. [28]

Therapeutic prospects include the possibility of selective modulation of angiogenic signals, targeted delivery of drugs to the placenta, and early identification of women at risk for placental dysfunction using molecular markers. These approaches are actively developing but require clinical trials. [29]

Table 4. Key molecules and their role in placental development

Molecule/pathway	Role	Clinical significance
VEGF / PLGF	Angiogenesis	Biomarkers of preeclampsia risk. [30]
Wnt / Notch	Differentiation of trophoblast	Control of EVT infestation. [31]
TGF-β	Migration control	Regulation of vascular remodeling. [32]
Epigenetics	Fine-tuning expression	Explains the influence of the environment on the development of the placenta. [33]

Clinical consequences of impaired placental formation

Disturbances in early placentation are associated with a range of complications, including preeclampsia, intrauterine growth restriction, preterm birth, and recurrent pregnancy loss. These conditions share a common pathophysiological basis, which is related to insufficient vascular remodeling and trophoblast dysfunction. [34]

Diagnosis of placental dysfunction is based on a combination of clinical findings, Doppler ultrasonography of the uterine and umbilical vessels, measurements of angiogenic markers in the maternal blood, and ultrasound assessment of fetal growth. Early identification allows for monitoring and interventions aimed at reducing perinatal risk. [35]

Preventive and therapeutic measures include low-dose aspirin for women at high risk of preeclampsia, monitoring and nutritional support for fetal growth restriction, and timing and route of delivery based on risk and fetal age. These approaches are based on randomized trials and guidelines. [36]

In the long term, placental developmental abnormalities are associated with an increased risk of cardiometabolic diseases in the offspring. This makes it important not only for acute management, but also for monitoring and preventing chronic conditions in the mother and child after birth. [37]

Table 5. Placental pathologies and key signs

Pathology	Mechanism	Clinical signs/diagnosis
Preeclampsia	Insufficient arterial remodeling	Arterial hypertension, proteinuria, PLGF/sFlt-1 abnormalities. [38]
Fetal growth restriction	Placental hypoperfusion	Low growth rate, Doppler pathology. [39]
Recurring losses	Early implantation defects	History of repeated losses, disruption of early markers. [40]

In-clinic placental assessment and imaging techniques

Ultrasound assessment remains the primary tool: early transvaginal imaging allows for the localization and structure of the chorionic node, and in subsequent trimesters, Doppler studies of the uterine and umbilical vessels are performed to assess perfusion. Doppler patterns correlate with the risk of placental insufficiency. [41]

Maternal blood biomarkers, such as the sFlt-1 to PLGF ratio, are used to predict the risk of preeclampsia and assess the severity of the condition; their use has become part of modern clinical algorithms in a number of health systems. [42]

If necessary, MRI of the placenta provides additional information on the structure and localization of pathologies, especially when obstetric anomalies of placental attachment are suspected and in complex clinical scenarios. Placental biopsy in the antenatal period is rarely performed and only for strictly weighed indications. [43]

New approaches include noninvasive spatially resolved transcriptomics and placenta-targeted biomarkers, which potentially enable early risk prediction and targeted interventions even before clinical manifestations. Technologies are advancing rapidly. [44]

Table 6. Placental assessment tools and their role

Method	When to use	What does it give?
Ultrasound + Doppler	Routinely, if suspected	Structure, blood flow, fetal growth. [45]
Plasma markers (sFlt-1/PLGF)	Risk of preeclampsia	Risk prediction and stratification. [46]
MRI	For complex attachments	Detailed anatomy of the placenta. [47]
Molecular tests	Knowledge-intensive centers	Early diagnosis, research purposes. [48]

Conclusion and practical implications

The placenta is formed through a complex interaction between embryonic trophoblasts and the maternal endometrium: successful placentation requires precise coordination of invasion, vascular remodeling, angiogenesis, and immune adaptation. Disruptions at any stage lead to clinical consequences for both mother and fetus. [49]

Early identification of women at risk for placental dysfunction, monitoring of perfusion and the use of biomarkers, and interdisciplinary approaches to managing complications are clinically important. Scientific technologies are opening new prospects for early diagnosis and targeted interventions. [50]

For practical work, it is recommended to: 1) assess risk factors before pregnancy; 2) conduct early ultrasound screening when indicated; 3) use Doppler and markers if placental insufficiency is suspected; 4) plan monitoring and timing of delivery individually. [51]