Chorionic villi are tiny, finger-like projections of tissue that extend from the outer membrane of a developing embryo into the wall of the uterus, forming the working surface of the placenta. They are where nearly everything critical in pregnancy happens at the cellular level: oxygen and nutrients pass from maternal blood to the fetus, waste products travel in the opposite direction, hormones are manufactured and secreted, and the immune system is carefully managed so that the mother’s body does not reject a genetically foreign fetus. These branching structures are also the tissue sampled during chorionic villus sampling, one of the earliest available prenatal diagnostic tests, and they have become a focus of research into pregnancy complications, infections, and even environmental contamination.
How Chorionic Villi Form and What They Do
Within the first two weeks after implantation, cells from the outer layer of the embryo, called trophoblasts, begin pushing into the uterine lining. These cells differentiate and organize into projections that branch repeatedly, creating an enormous surface area packed into a small space. The placenta is primarily composed of trophoblasts that differentiate into villi, along with stromal cells, immune cells called macrophages, and fetal endothelial cells that line the blood vessels running through each villus core.1PubMed Central. Human Chorionic Villous Differentiation and Placental Development By the end of the first trimester, there are millions of villi, and their total exchange surface area rivals that of a small room.
Each villus works like a miniature supply depot. Maternal blood flows into spaces surrounding the villi, and across the thin trophoblast barrier, dissolved oxygen, glucose, amino acids, and other nutrients diffuse or are actively transported into fetal capillaries embedded in the villus core. Carbon dioxide and metabolic waste move the other direction. The system is remarkably efficient given that maternal and fetal blood never actually mix; the trophoblast layer keeps them separated while still allowing rapid exchange.
Hormone Production Inside the Villi
Beyond nutrient transfer, chorionic villi are a major endocrine organ. The trophoblast cells lining each villus produce human chorionic gonadotropin (hCG), the hormone detected by pregnancy tests, as well as progesterone and other hormones necessary to maintain the pregnancy. Research using cultured villi has shown that when chorionic tissue is maintained in conditions mimicking the natural tissue environment, production of hCG, progesterone, and pregnancy-associated plasma protein A remains higher and lasts longer than in other culture conditions.2PubMed. Extracellular matrix influences hormone and protein production by human chorionic villi
Progesterone production is particularly interesting because it begins in the villous cytotrophoblasts, the inner layer of trophoblast cells, before they fuse into the outer syncytiotrophoblast layer. Both progesterone and its precursor, pregnenolone, are made by those inner cells, and their secretion increases as the cells fuse and mature.3PubMed. Placental production of progestins is fully effective in villous cytotrophoblasts and increases with the syncytiotrophoblast formation This means the villi are producing the very hormone needed to sustain pregnancy from quite early in their development.
Chorionic Villus Sampling as a Diagnostic Tool
Because chorionic villi share the fetus’s genetic makeup (both originate from the same fertilized egg), a small sample of villus tissue can be tested for chromosomal abnormalities, genetic disorders, and biochemical conditions. This procedure, chorionic villus sampling or CVS, is typically performed between ten and fourteen weeks of pregnancy, making it one of the earliest invasive prenatal tests available. When performed in that window, CVS is both safe and effective for diagnosing chromosomal, biochemical, and molecular disorders, with risks comparable to those of second-trimester amniocentesis.4PubMed. First trimester prenatal diagnosis: chorionic villus sampling
Early concerns about a possible link between CVS and limb defects in the fetus have been substantially addressed by accumulated data showing minimal to no risk when the procedure is performed after 70 days of gestation.5PubMed. First trimester prenatal diagnosis: chorionic villus sampling The procedure-related pregnancy loss rate has been studied in large cohorts. In one study, pregnancy loss occurred in about 1% of CVS cases, which was not statistically different from the rate in a matched control group that did not undergo an invasive procedure.6PubMed Central. Pregnancy Loss After Amniocentesis and Chorionic Villus Sampling: Cohort Study A large national registry study found the rate of fetal loss after CVS to be somewhat higher, though that study included a wider gestational age range and did not use matched controls in the same way.7PubMed. Complication rates after chorionic villus sampling and midtrimester amniocentesis: A 7-year national registry study
Timing within the standard window does not greatly affect the practicalities of the test. A recent study comparing early, typical, and late CVS procedures found that the amount of tissue collected was comparable across groups, and adequate samples were obtained in over 89% of cases regardless of gestational age.8PubMed Central. Chorionic Villi Sampling among Early and Late Gestational Age: Does Timing Affect Yield and Outcomes?
The Mosaicism Problem
One quirk of testing chorionic villi rather than the fetus directly is that the placenta can carry genetic abnormalities the fetus does not have, and vice versa. This phenomenon, called confined placental mosaicism, happens because the villi and the embryo proper diverge early in development, and genetic errors that arise in one lineage may not be present in the other. A large European collaborative study found that confined placental mosaicism occurred in about 1% of CVS samples, while true fetal mosaicism (where the abnormality was confirmed in the fetus) was found in only about 0.15%.9PubMed. Accuracy of cytogenetic findings on chorionic villus sampling (CVS)–diagnostic consequences of CVS mosaicism and non-mosaic discrepancy in centres contributing to EUCROMIC 1986-1992
Put differently, only about 23% of mosaicism detected at CVS is actually confirmed in the fetus, meaning most abnormal cell lines found in chorionic villi are an inaccurate prediction of the fetal genotype.10PubMed. Chromosomal mosaicism in chorionic villus sampling This is why an abnormal CVS result often prompts follow-up amniocentesis to check the fetal cells directly. The false-positive rate for common chromosome abnormalities in the cytotrophoblast layer ranges widely depending on the degree of mosaicism, while false negatives are rarer.11Genetics in Medicine. Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results The mosaicism issue also has implications for noninvasive prenatal screening (NIPT), because the cell-free DNA that circulates in the mother’s blood and is analyzed by those blood tests is actually shed from chorionic villi, not from the fetus itself.
Cell-Free Fetal DNA Actually Comes from the Villi
This is a point that surprises many people. The “fetal DNA” detected in a pregnant person’s blood during NIPT is, in the vast majority, placental DNA. The constant turnover of the trophoblast layer on chorionic villi results in the extrusion of dying cells and their DNA fragments into the maternal bloodstream.12PubMed Central. Review: cell-free fetal DNA in the maternal circulation as an indication of placental health and disease Most of this DNA circulates in small membrane-bound packages called apoptotic bodies.13Human Reproduction Update. Cell-free fetal DNA in maternal blood: kinetics, source and structure Because chorionic villi normally share the fetus’s genetic code, the distinction is academic in most pregnancies. But in cases of confined placental mosaicism, it can lead to a discordant NIPT result: the blood test reads the placenta’s DNA, which may not match the fetus. Clinicians keep this in mind when interpreting unexpected NIPT results.
How the Villi Keep the Immune System in Check
A fetus is genetically half foreign to the mother’s immune system, which should, in theory, provoke rejection. One of the ways the placenta prevents this is through the expression of an unusual immune molecule called HLA-G on its chorionic villi. Unlike the common HLA-A and HLA-B molecules that flag cells for immune recognition and are switched off in trophoblast cells, HLA-G is expressed throughout pregnancy.14Human Reproduction Update. The major histocompatibility complex in pregnancy: Part II. Placental HLA-G protein expression in vivo: where and what for? HLA-G interacts with receptors on maternal immune cells that inhibit killing, essentially telling the mother’s immune system to stand down.
Intriguingly, HLA-G has also been found on the endothelial cells lining fetal blood vessels inside chorionic villi during the first trimester, suggesting it may play a role in the formation of new blood vessels within the placenta itself, beyond just immune suppression.15PubMed. Endothelial cells in chorionic fetal vessels of first trimester placenta express HLA-G
When the Villi Malfunction in Pregnancy Complications
Because chorionic villi are the functional units of the placenta, problems with their development or the blood vessels supplying them can underlie serious pregnancy complications. In preeclampsia and fetal growth restriction, a common finding is that the mother’s spiral arteries, which deliver blood to the spaces around the villi, fail to remodel properly. Normally, invasive trophoblast cells from the villi burrow into these arteries and widen them into low-resistance channels. When that remodeling is defective, the villi receive less blood, and the resulting poor oxygen delivery can trigger a cascade of problems. Studies of placental bed biopsies have confirmed that spiral artery remodeling is significantly reduced in both preeclampsia and fetal growth restriction, and that this defect correlates with clinical severity.16PubMed. Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome
Within the villi themselves, reduced blood flow triggers abnormal responses. In growth-restricted pregnancies, the expression of growth factors involved in building new blood vessels is elevated, suggesting the placenta is trying to compensate for poor perfusion by stimulating more vessel formation.17PubMed Central. Intrauterine growth restriction and placental angiogenesis In preeclampsia specifically, VEGF-A, a key molecule that drives blood vessel growth and is known to be upregulated by low oxygen, is elevated roughly threefold compared to normal third-trimester placentas.18The Journal of Clinical Endocrinology & Metabolism. Human Placental Vascular Development: Vasculogenic and Angiogenic (Branching and Nonbranching) Transformation Is Regulated by Vascular Endothelial Growth Factor-A, Angiopoietin-1, and Angiopoietin-2
Villitis, Infections, and Immune Breakdown
Sometimes the villi become inflamed, a condition called villitis. When a known infection is responsible, such as cytomegalovirus or toxoplasmosis, the cause is clear. But in many cases no pathogen is identified, and the condition is labeled villitis of unknown etiology, or VUE. This is a common placental finding at term and is associated with fetal growth restriction, preterm birth, and recurrent pregnancy loss.19PubMed. The immunological basis of villitis of unknown etiology – review
The leading theory for VUE is not an undiagnosed infection but rather a breakdown of the immune tolerance that normally protects the fetus. Researchers have found that both maternal and fetal immune cells infiltrate the villi, and the pattern bears some resemblance to transplant rejection or graft-versus-host disease.20PubMed. The immunological basis of villitis of unknown etiology – review That said, a viral contribution has not been entirely ruled out. One study found that half of VUE placentas contained at least one herpesvirus (such as Epstein-Barr virus or cytomegalovirus), compared with only 10% of control placentas, and antiviral immune pathways were activated in the affected tissue.21PubMed Central. Chronic Villitis of Unknown Etiology: Investigations into Viral Pathogenesis Whether these viruses are a cause of the inflammation or merely bystanders reactivated by the disturbed immune environment remains an open question.
Chorionic villi are also a key battleground in vertically transmitted infections. During the Zika virus epidemic, researchers used first-trimester villus explant cultures to show that the virus could infect several cell types within the villi, including proliferating cytotrophoblasts and Hofbauer cells, the resident placental macrophages.22Cell Host & Microbe. Zika Virus Infects Human Placental Tissues and Respective Primary Cells and Demonstrates Gestational Age-Dependent Susceptibility Infected cytotrophoblasts stopped proliferating, and the virus appeared to spread from cell to cell within the villus tissue. Multiple routes for the virus to cross the placental barrier have been proposed, including direct transplacental passage, movement between cells, and transport within small vesicles.23PubMed. Possible Routes for Zika Virus Vertical Transmission in Human Placenta: A Comprehensive Review
Hydatidiform Moles and Placenta Accreta
Two other conditions center directly on chorionic villi behaving abnormally. A hydatidiform mole occurs when fertilization goes wrong, resulting in an overexpression of the paternal genetic contribution. The villi swell with fluid, a process called hydropic change. In a complete mole, virtually all villi become grossly enlarged, and when a central fluid-filled cavity forms within a villus, it is termed a cistern. In a partial mole, there are two populations of villi: some large and hydropic, others normal-sized. The villi in a partial mole show characteristic surface irregularities, with scalloping and deep invaginations that create a distinctive appearance under the microscope.24Diagnostic Histopathology. Hydatidiform moles and mimics: an up-to-date review on morphology and immunocytochemistry to aid the diagnosis
Placenta accreta spectrum disorders involve villi attaching too deeply to the uterine wall. In the mildest form, villi simply adhere to the muscle layer of the uterus. In the more severe form, increta, villi invade into the muscle. In the most extreme, percreta, villi penetrate the full thickness of the uterine wall.25PubMed. Placenta accreta spectrum: pathophysiology and evidence-based anatomy for prenatal ultrasound imaging These conditions are becoming more common, largely because of rising cesarean section rates. Scar tissue from a previous cesarean appears to facilitate abnormally deep trophoblast invasion.26Clinical Obstetrics and Gynecology. Pathophysiology of Placenta Accreta Spectrum Disorders: A Review of Current Findings The result can be life-threatening hemorrhage at delivery.
Microplastics in Chorionic Villi
A growing and unsettling area of research involves the detection of microplastics in placental tissue. In a recent study of first-trimester chorionic villi from women who experienced unexplained miscarriage, microplastics were detected in every single sample analyzed. The average total concentration was roughly 250 micrograms per gram of tissue, with PVC and polyethylene being the most abundant types.27EBioMedicine. Detection and quantification of microplastics in human chorionic villi and their association with unexplained spontaneous miscarriage Separately, laboratory experiments using term placental tissue showed that polystyrene microplastic particles were not just sitting on the villus surface but were internalized into the syncytiotrophoblast layer and found up to 120 micrometers deep within the villus tissue over 72 hours.28PubMed Central. Polystyrene microplastics internalization by term placental chorionic villi explants
Whether microplastics in the placenta contribute to pregnancy complications remains unclear. The finding that they reach the maternal-fetal interface and accumulate during early gestation is itself significant, but establishing a causal link to miscarriage or other outcomes will require much more research. What is clear is that the chorionic villi, designed to be permeable enough to transfer nutrients, are also permeable to particles that were never supposed to be there.
Epigenetic Signatures in the Villi and Recurrent Miscarriage
Researchers studying recurrent miscarriage have found that chorionic villi from affected pregnancies carry distinctive chemical modifications to their DNA, specifically in the pattern of methyl groups attached to the genetic code. These methylation patterns were clearly different from those in villi from normal pregnancies, and the distinction was visible across gene promoters, enhancers, and gene body regions. Interestingly, the same clear differences were not found in decidua, the maternal side of the implantation site, suggesting the problem is specific to the fetal-placental tissue.29Scientific Reports. Characteristic DNA methylation profiles of chorionic villi in recurrent miscarriage
Some of these methylation changes affect imprinted genes, which are genes where only the copy from one parent is active. In chorionic villi from recurrent miscarriage cases, certain imprinted gene regions showed lower-than-normal methylation.30PeerJ. Comprehensive analysis of DNA methylation patterns in recurrent miscarriage: imprinted/non-imprinted genes and their regulation across sperm and fetal-maternal tissues Two large clusters of small regulatory RNA molecules on chromosomes 14 and 19, which help control trophoblast growth and movement, also showed abnormally low methylation in the villi of recurrent miscarriage cases.31PubMed. Methylation Status at DMRs of C14MC and C19MC in Spermatozoa and Chorionic Villi of Individuals Experiencing Recurrent Spontaneous Abortions These findings point toward epigenetic dysfunction in the villi as one potential contributor to pregnancy loss, though the field is still working out which changes are causes and which are consequences.
Villi Across Species
Chorionic villi are not unique to humans. They have evolved independently in several mammalian lineages, including horses. But the villi in different species are not carbon copies. A comparative imaging study found that horse placental villi have a substantially higher surface-area-to-volume ratio than human villi, and their blood vessels are indented more deeply into the villus tissue, creating shorter distances between the trophoblast layer and the fetal blood.32PubMed Central. Convergently evolved placental villi show multiscale structural adaptations to differential placental invasiveness Modeling suggests these deeper indentations in horse villi would particularly benefit the transfer of substances that depend on transporter proteins in cell membranes, like amino acids, rather than simple gas diffusion.
The human placenta is classified as hemochorial, meaning maternal blood directly bathes the trophoblast surface. The horse placenta is epitheliochorial, with more tissue layers separating maternal and fetal blood. The structural differences in the villi appear to compensate for these different levels of invasiveness, producing adaptations fine-tuned to each species’ particular anatomy. It is a striking example of convergent evolution arriving at the same basic solution, branching tissue projections, while tuning the details to different physiological constraints.
Building Artificial Villi in the Lab
One reason chorionic villi remain so difficult to study is that they exist inside a living pregnancy and cannot be easily observed in real time. Researchers have responded by developing increasingly sophisticated lab models. Recent work includes organ-on-a-chip platforms that combine trophoblast cell clusters with endothelial cells under conditions that mimic blood flow and mechanical stretching. One such model was able to form a three-dimensional barrier resembling the placental surface, complete with the expression of syncytiotrophoblast markers, hCG secretion, and glucose transport activity.33PubMed. An Integrated Organoid-on-a-Chip Platform for Modeling the Human Placental Barrier Earlier work using stem cells attempted to induce villous differentiation from scratch, producing structures that could be used for research that would be impossible in living pregnancies.34PubMed Central. Human Chorionic Villous Differentiation and Placental Development
These technologies are opening doors to studying drug transport across the placental barrier, testing how environmental contaminants interact with trophoblast tissue, and modeling the earliest stages of placental disease. For a structure that has historically been examined only after delivery or miscarriage, the ability to recreate functioning villi outside the body represents a genuine shift in what pregnancy research can accomplish.