Placenta

Nonneoplastic placental conditions and abnormalities

Infectious

COVID-19 placentitis



Last author update: 3 February 2022
Last staff update: 3 February 2022

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PubMed Search: COVID-19 placentitis pathology review[PT]

Sanjita Ravishankar, M.D.
Jonathan L. Hecht, M.D., Ph.D.
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Cite this page: Ravishankar S, Hecht JL. COVID-19 placentitis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/placentaCOVID-19placentitis.html. Accessed July 3rd, 2022.
Definition / general
  • Pattern of injury associated with transplacental maternal - fetal transmission of SARS-CoV-2
  • Chronic histiocytic intervillositis with trophoblast necrosis in placentas with documented viral infection by SARS-CoV-2
Essential features
  • Vast majority of placentas from mothers infected by SARS-CoV-2 show no specific gross of histologic findings regardless of maternal symptom severity or bulk detection of virus in the placenta
  • COVID-19 placentitis occurs in 1 - 3% of placentas of infected mothers and is associated with transplacental maternal - fetal transmission of SARS-CoV-2
  • Data is inconsistent regarding association of other patterns of placental injury (maternal or fetal vascular malperfusion) with maternal COVID infection, regardless of documented virus in the placenta
ICD coding
  • ICD-10:
    • O41.1410 - placentitis, first trimester
    • O41.1420 - placentitis, second trimester
    • O41.1430 - placentitis, third trimester
Epidemiology
Sites
  • Placenta
Pathophysiology
  • Pregnancies affected by COVID infection fall into 3 categories:
    • Group 1: infected placentas with infected neonates (vertical transmission)
    • Group 2: uninfected placentas from mothers with recent (< 14 days) COVID infection
    • Group 3: uninfected placentas from mothers with remote COVID infection
  • COVID placentitis occurs only in a subset of group 1
  • Main placental cell type supporting viral replication is the syncytiotrophoblast
  • Infection requires expression of the viral receptor angiotensin converting enzyme receptor 2 (ACE2) and the TMPRSS2 protease
  • Placentitis may arise due to direct cytotoxicity by active viral replication in the syncytiotrophoblast or immune mediated damage secondary to inflammatory / cytokine response to COVID-19 infection
  • Other patterns of injury:
    • Fetal vascular malperfusion (fetal thrombosis) may be more frequent among the acute SARS-CoV-2 (group 2) as compared to the nonacute SARS-CoV-2 group (53.8% versus 18.8%; P = 0.002) (Am J Surg Pathol 2022;46:51)
      • Overall, the literature does not provide strong support
    • Maternal SARS-CoV-2 infection early in gestation (group 3) may be associated with pregnancy complications related to implantation, such as preeclampsia and stillbirth, and histologic lesions of maternal vascular malperfusion (BJOG 2020;127:1374, Eur J Obstet Gynecol Reprod Biol 2020;252:559, Am J Obstet Gynecol MFM 2020;2:100107)
      • Evidence for maternal malperfusion is controversial:
        • Infection has been demonstrated in vitro in trophoblastic stem cells suggesting the possibility of preimplantation effects of infection and that the viral receptor ACE2 is required for normal decidualization and implantation
        • However, the overall literature supports only a weak association (Front Immunol 2021;12:685919)
        • In one study, the frequency of maternal vascular malperfusion did not differ by timing of infection (30.8% recent versus 29.7% remote; P > 0.99) (Am J Surg Pathol 2022;46:51)
    • Other currently unsupported theories of a placental role in pregnancy complications during COVID infection include:
      • Placenta might serve as a viral reservoir after clinical recovery in the respiratory tract, leading to chronic placental injury or maternal inflammatory state as manifested by maternal hypertension (Fetal Diagn Ther 2021 Nov 18 [Epub ahead of print])
      • Altered renin angiotensin signaling
        • ACE2, the viral receptor, is expressed in a soluble form shed by the placenta in third trimester via cleavage by ADAM17 enzyme
        • This shedding is increased in women with COVID-19 infection and theoretical systemic effects on blood pressure or renal function (bioRxiv 2021 Nov 22 [Preprint])
Etiology
  • No known risk factors for placental viral spread and COVID placentitis among women with SARS-CoV-2 infection
  • Lesions of maternal vascular malperfusion, gestational hypertension, preeclampsia and stillbirth may be more frequently detected in mothers with COVID infection due to the similarity in risk factors for these lesions and severe viral illness
Laboratory
  • Documentation of maternal SARS-CoV2 is an indication for placental examination but is not required for the diagnosis of COVID placentitis
Prognostic factors
  • Cases of fetal transmission are almost always associated with COVID-19 placentitis; however, specificity and sensitivity of COVID placentitis for fetal infection and poor clinical outcome is low (Arch Pathol Lab Med 2021;145:1341)
Case reports
  • 23 year old woman, gravida 1, at 35 + 2 weeks gestation delivered on day 3 of admission for moderately severe COVID and category III fetal heart rate tracing (Nat Commun 2020;11:3572)
  • 28 year old woman, gravida 4 para 3, with fetal demise of diamniotic twin pregnancy at 13 weeks and moderate symptomatic COVID (24 hour admission) (J Med Virol 2021;93:4480)
  • 29 and 34 year old women with decreased fetal movements and abnormal fetal heart rhythm 5 days after mild maternal COVID-19, requiring emergency caesarean section at 29 + 3 and 32 + 1 weeks of gestation and leading to brain injury (Viruses 2021;13:2517)
  • 30 year old woman, gravida 2 para 1, with dichorionic diamniotic twins and gestational diabetes mellitus and asymptomatic COVID on screening nasal swab at 22 weeks gestation (Eur J Clin Microbiol Infect Dis 2020;39:2441)
  • 35 year old woman in second trimester with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption (J Clin Invest 2020;130:4947)
  • 37 year old woman, gravida 4 para 3, at 34 weeks gestation with large for gestational age female infant due to diabetes and obesity (Pediatr Infect Dis J 2020;39:e265)
Treatment
  • Viral testing and close monitoring of newborns is indicated
Gross description
  • Placentas affected by COVID placentitis often show tan-yellow, firm areas that involve a significant percentage (often > 50%) of the placental parenchyma, similar to the appearance seen in massive perivillous fibrin deposition
Gross images

Contributed by Sanjita Ravishankar, M.D.
Pale consolidation of disc Pale consolidation of disc

Pale consolidation of disc

Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Sanjita Ravishankar, M.D.
Perivillous fibrin deposition and intervillous thrombus

Perivillous fibrin deposition and intervillous thrombus

Perivillous fibrin deposition and trophoblast necrosis

Perivillous fibrin deposition and trophoblast necrosis

Perivillous fibrin deposition and chronic intervillositis Perivillous fibrin deposition and chronic intervillositis

Perivillous fibrin deposition and chronic intervillositis

Chronic intervillositis and trophoblast necrosis

Chronic intervillositis and trophoblast necrosis


Syncytiotrophoblast are IHC positive for COVID-19 capsid protein

COVID-19 capsid protein

Positive stains
  • Immunohistochemistry may be used for detection of viral infection but diagnosis of COVID placentitis also requires the histologic pattern (Am J Obstet Gynecol 2021;225:593.e1)
  • Positive immunohistochemistry for COVID-19 is supportive but is not necessary for the diagnosis of COVID placentitis in the presence of the characteristic histologic findings
Electron microscopy description
Molecular / cytogenetics description
  • Placental infection may be detected using in situ hybridization with antisense probe (detects replication) or a sense probe (detects viral messenger RNA) or immunohistochemistry to detect viral nucleocapsid or spike proteins (least specific)
    • Not preferred are bulk viral RNA load in placental homogenates or electron microscopy
    • See examples in Case reports
  • Graded classification for the likelihood of placental infection (definitive, probable, possible and unlikely) was proposed at an NIH consensus conference (Am J Obstet Gynecol 2021;225:593.e1)
    • Definitive: evidence of active replicating virus with location in the placental tissues
    • Probable: evidence of viral RNA or protein located in placental tissues
    • Possible: evidence of viral RNA in placental homogenates or viral-like particles by electron microscopy in placental tissues
    • Unlikely: no evidence of any of the above
    • No testing: testing not done
Sample pathology report
  • Placenta:
    • Diffuse acute and chronic intervillositis with associated perivillous fibrin deposition and trophoblast necrosis, consistent with COVID-19 placentitis
Differential diagnosis
  • Chronic histiocytic intervillositis:
    • Diffuse histiocytic infiltrate in intervillous space with variable perivillous fibrin
    • Lacks prominent trophoblast necrosis
    • Usually small placenta and intrauterine growth restriction (IUGR) rather than acute maternal viral syndrome
    • IHC for SARS-CoV-2 is negative; no evidence of malaria
  • Placental infarction:
    • Aggregated necrotic villi; may be associated with hematoma
    • Intervillous histiocytes are not prominent as in COVID placentitis
    • Gross lesions are typically circumscribed and varying in age (red, yellow); COVID placentitis is more diffuse and poorly circumscribed
Additional references
Board review style question #1
A placenta was delivered to a mother with recent hospital admission for COVID pneumonia. The minimal diagnostic features required for COVID placentitis are

  1. Chronic histiocytic intervillositis and trophoblast necrosis and documentation of recent maternal infection via nasal swab
  2. Chronic villitis of uncertain etiology (VUE) with documented placental infection by SARS-CoV-2 by ISH
  3. Evidence of maternal vascular malperfusion and preeclampsia and documentation of recent maternal infection via nasal swab
  4. Fetal vascular malperfusion with documented placental infection by SARS-CoV-2 by ISH
Board review style answer #1
A. Chronic histiocytic intervillositis and trophoblast necrosis and documentation of recent maternal infection via nasal swab

Comment Here

Reference: COVID-19 placentitis
Board review style question #2
Which is the best predictor of fetal / neonatal SARS-CoV-2?

  1. Chronic histiocytic intervillositis and trophoblast necrosis in placentas with documented placental infection by SARS-CoV-2 by ISH
  2. Fetal demise in the setting of maternal COVID infection
  3. High grade chronic villitis of uncertain etiology (VUE) in a mother with severe clinical COVID viral syndrome
  4. Maternal infection with a severe clinical viral syndrome
Board review style answer #2
A. Chronic histiocytic intervillositis and trophoblast necrosis in placentas with documented placental infection by SARS-CoV-2 by ISH

Comment Here

Reference: COVID-19 placentitis
Board review style question #3

The findings depicted in this image are

  1. Chronic histiocytic intervillositis and trophoblast necrosis (COVID placentitis)
  2. Chronic villitis of uncertain etiology (VUE)
  3. Fetal vascular malperfusion; villous sclerosis and stem vessel thrombosis
  4. Maternal vascular malperfusion; infarction and accelerated maturation
Board review style answer #3
A. Chronic histiocytic intervillositis and trophoblast necrosis (COVID placentitis)

Comment Here

Reference: COVID-19 placentitis
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