Definition/General
Introduction:
Chronic intervillositis (CIV) is characterized by mononuclear inflammatory infiltrate in the intervillous space
It involves histiocytes and lymphocytes surrounding chorionic villi
It represents maternal immune response in the intervillous space
It is associated with recurrent pregnancy loss.
Origin:
Pathogenesis involves maternal immune dysfunction
Autoimmune mechanisms may be involved
Infectious triggers (malaria, CMV) in some cases
Maternal alloimmune response to fetal antigens
Results in intervillous space inflammation
Complement activation may play a role.
Classification:
Classified by severity: Mild, moderate, severe
By cell type: Histiocytic vs lymphocytic predominance
By associated features: With/without villous necrosis
Malaria-associated vs idiopathic forms.
Epidemiology:
Rare condition with incidence <1% of pregnancies
Higher incidence in malaria-endemic areas
Associated with recurrent pregnancy loss (up to 90% recurrence)
More common in sub-Saharan Africa
Increasing recognition worldwide.
Clinical Features
Presentation:
Recurrent pregnancy loss (most characteristic)
Severe intrauterine growth restriction
Stillbirth
Preterm delivery
Maternal anemia (malaria-associated cases)
Often poor pregnancy outcomes across multiple pregnancies.
Symptoms:
History of multiple pregnancy losses
Severe fetal growth restriction in current pregnancy
Maternal symptoms may be minimal
Fever and malaise (malaria cases)
Decreased fetal movements
Signs of chronic fetal hypoxia.
Risk Factors:
Previous pregnancy with CIV (high recurrence rate)
Malaria exposure (endemic areas)
Autoimmune disorders
Maternal immunological abnormalities
Consanguinity (some reports)
Advanced maternal age.
Screening:
Detailed pregnancy history (recurrent losses)
Malaria screening (endemic areas)
Autoimmune workup
Fetal growth monitoring
Enhanced prenatal surveillance
Placental examination essential for diagnosis.
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Gross Description
Appearance:
Placenta shows decreased weight for gestational age
Firm, pale areas throughout parenchyma
Granular cut surface
May show areas of hemorrhage
Maternal surface may appear irregular.
Characteristics:
Markedly decreased placental weight
Firm consistency throughout
Pale, gray discoloration
Cut surface shows granular texture
Loss of normal spongy consistency
May have focal hemorrhagic areas.
Size Location:
Typically involves entire placenta (diffuse pattern)
Uniform involvement of all cotyledons
No preferential location
Extensive distribution
Chorionic plate usually spared.
Multifocality:
Shows diffuse, uniform involvement
Not typically multifocal
Confluent pattern throughout placenta
No skip lesions
Homogeneous distribution.
Microscopic Description
Histological Features:
Dense mononuclear infiltrate in intervillous space
Histiocytes and lymphocytes surrounding villi
Villous surface fibrin deposition
Villous agglutination
Syncytiotrophoblast damage
Intervillous fibrin thrombi.
Cellular Characteristics:
Inflammatory cells predominantly CD68+ histiocytes
CD3+ T-lymphocytes
Plasma cells may be present
Foamy macrophages (malaria cases)
Giant cells occasionally
Hemosiderin-laden macrophages.
Architectural Patterns:
Intervillous space obliteration by inflammatory cells
Villous agglutination and fusion
Fibrin deposition between villi
Loss of intervillous circulation
Villous surface denudation
Chronic deciduitis may coexist.
Grading Criteria:
Mild: Scattered inflammatory cells in intervillous space
Moderate: Moderate density with focal villous agglutination
Severe: Dense infiltrate with extensive villous agglutination
Based on inflammatory cell density.
Immunohistochemistry
Positive Markers:
CD68 (histiocytes, predominant cell type)
CD3 (T-lymphocytes)
CD20 (B-lymphocytes, if present)
CD138 (plasma cells)
HAM56 (histiocytes)
Complement components (C3, C4).
Negative Markers:
Neutrophil markers (CD15, MPO) typically absent
Eosinophil markers usually negative
Viral antigens (unless coinfection)
Bacterial stains negative.
Diagnostic Utility:
CD68 highlights histiocytic infiltrate
Confirms mononuclear nature of inflammation
Distinguishes from acute inflammation
Quantifies inflammatory response
Essential for accurate diagnosis.
Molecular Subtypes:
Malaria-associated CIV: Plasmodium pigment present
Idiopathic CIV: No identifiable cause
CMV-associated CIV: Viral inclusions present
Autoimmune-associated forms.
Molecular/Genetic
Genetic Mutations:
No specific genetic mutations identified
HLA associations reported in some families
Complement system variants
Maternal immune response genes
Familial clustering suggests genetic factors.
Molecular Markers:
Complement activation markers
Autoantibodies (anticardiolipin, anti-β2GP1)
Inflammatory cytokines (TNF-α, IL-1β)
HLA typing
Malaria antigen detection (endemic areas).
Prognostic Significance:
Very high recurrence rate (up to 90%)
Poor fetal outcomes in affected pregnancies
Associated with stillbirth
Severe growth restriction
Limited treatment options.
Therapeutic Targets:
Antimalarial prophylaxis (endemic areas)
Immunosuppressive therapy (experimental)
Low-dose aspirin
Corticosteroids (limited evidence)
Enhanced prenatal surveillance
Early delivery may be considered.
Differential Diagnosis
Similar Entities:
Villitis of unknown etiology (villous stromal involvement)
Chronic villitis (inflammatory cells within villi)
Massive perivillous fibrin deposition
Maternal floor infarction
Placental malaria.
Distinguishing Features:
CIV: Intervillous space inflammation
CIV: Villi surrounded by inflammatory cells
Villitis: Inflammation within villous stroma
MPFD: Fibrin without significant inflammation
MFI: Fibrin deposition at maternal floor.
Diagnostic Challenges:
Distinguishing from other chronic inflammatory conditions
Recognition of intervillous space involvement
Adequate sampling essential
Correlation with clinical history of pregnancy losses
Ruling out infectious causes.
Rare Variants:
CIV with villous necrosis
Plasma cell-rich CIV
Giant cell CIV
Combined CIV and villitis
Familial recurrent CIV.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Placenta weighing [weight]g ([percentile] for GA) with diffuse inflammatory changes
Diagnosis
Chronic Intervillositis
Classification
Classification: [Mild/Moderate/Severe] chronic intervillositis with [histiocytic/lymphocytic] predominance
Histological Features
Shows dense mononuclear inflammatory infiltrate in intervillous space with villous agglutination
Immunohistochemistry
CD68: Positive (histiocytes), CD3: Positive (T-lymphocytes), confirming mononuclear infiltrate
Severity Grading
Severity: [Grade] based on inflammatory density and villous agglutination extent
Clinical Correlation
Consistent with history of [recurrent pregnancy loss/growth restriction]. Associated with poor fetal outcomes.
Recurrence Risk
High recurrence risk (up to 90%) in subsequent pregnancies. Enhanced surveillance recommended.
Final Diagnosis
Chronic Intervillositis, [Grade], with high recurrence risk and poor fetal prognosis