Clinical Significance of Increased Syncytial Knots
Increased syncytial knots are a histologic marker of placental malperfusion and maternal vascular insufficiency, signaling either advanced placental maturation or pathologic conditions such as preeclampsia, fetal growth restriction, and placenta accreta spectrum disorders.
Pathophysiology and Formation
Syncytial knots are aggregates of syncytiotrophoblast nuclei at the surface of terminal villi that increase progressively with gestational age 1. Their formation is induced by oxidative stress, hypoxia, and hyperoxia, with experimental evidence demonstrating increased syncytial knot formation when placental tissue is exposed to these conditions 2. The mechanism involves syncytiotrophoblast stress rather than simple apoptosis, as anti-apoptotic proteins (Bcl-2, Mdm2, XIAP, survivin) remain present in regions with syncytial knots 2.
Normal Reference Values by Gestational Age
Understanding normal values is critical to identifying pathologic increases 1:
- 20-25 weeks: 5.2-9.1% of villi with syncytial knots 1
- 26-33 weeks: 10.8-14.7% of villi with syncytial knots 1
- 36 weeks: Mean of 22.5% 1
- 37-40 weeks (term): Average of 28-30% of terminal villi with syncytial knots 1
Clinical Associations and Pathologic Significance
Maternal Vascular Malperfusion
Increased syncytial knots are a hallmark feature of maternal vascular malperfusion (MVM) and are associated with multiple placental pathologies 3. In the context of basal plate myofibers (a form of placenta accreta spectrum), increased syncytial knots occur alongside other MVM lesions including decreased placental weight, abnormal uteroplacental vessels, villous agglutination, increased perivillous fibrin, and infarction 3.
Preeclampsia and Hypertensive Disorders
Syncytiotrophoblast stress manifests as increased syncytial knots in both early-onset and term preeclampsia 3. In term preeclampsia, where abnormal spiral artery remodeling is typically absent, the increased syncytial knots reflect a placenta that has reached the limits of its functional reserves rather than primary vascular abnormalities 3.
Iatrogenic Preterm Birth
In iatrogenic preterm birth (IPTB), increased syncytial knots are significantly elevated (81% of cases with infants alive at one year) compared to spontaneous preterm birth 4. This finding is part of a constellation of MVM features including distal villous hypoplasia, decidual arteriopathy, and increased perivillous fibrin 4. Notably, increased syncytial knots were present in only 26% of preterm stillbirths and 29% of preterm infant demises, suggesting their presence may paradoxically indicate some degree of placental adaptive capacity 4.
Endometriosis-Related Placental Pathology
Women with endometriosis-related infertility who conceive via ART demonstrate higher rates of increased syncytial knotting and vascular malperfusion disorders including subchorionic and perivillous fibrin deposition and intervillous thrombosis 5. After adjusting for confounding factors, endometriosis remains independently associated with increased syncytial knot formation 5.
Diagnostic Interpretation Challenges
Quantifying syncytial knots requires standardized methodology to achieve reproducibility 6. Interrater reliability is best for preterm placentas (kappa = 0.61) and when diffuse prominent syncytial knots are associated with a specific lesion (kappa = 0.67) 6. Agreement is poor when syncytial knots are minimal (kappa = 0.22) or when present without an associated lesion (kappa = 0.32) 6.
Clinical Management Implications
When increased syncytial knots are identified on placental pathology:
- Correlate with clinical risk factors including hypertensive disorders, fetal growth restriction, and prior cesarean delivery with suspected placenta accreta spectrum 3
- Recognize this as a marker of uteroplacental malperfusion that may have contributed to adverse pregnancy outcomes 1, 2, 4
- Consider implications for future pregnancies, particularly in the context of basal plate myofibers where recurrence risk for placenta accreta spectrum is elevated 3
- Document the finding quantitatively when possible, comparing to gestational age-specific reference values 1
Common Pitfalls
- Do not interpret syncytial knots in isolation—they must be evaluated in the context of gestational age, clinical history, and other placental lesions 1, 6
- Avoid over-interpretation at term, where up to 30% of villi normally contain syncytial knots 1
- Recognize that most syncytial knots at term are tangential sectioning artifacts rather than true pathologic structures 1
- Understand that absence of hypertensive disorders does not exclude maternal vascular malperfusion, as demonstrated in basal plate myofiber cases where increased syncytial knots occur without documented hypertension 3