Study suggests cortical hemorrhage in fetal brain may be associated with COVID-19

In a recent study published in BRAIN, researchers evaluated the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on fetal brain health.

Study: Haemorrhage of human foetal cortex associated with SARS-CoV-2 infection. Image Credit: Prostock-studio/Shutterstock
Study: Haemorrhage of human foetal cortex associated with SARS-CoV-2 infection. Image Credit: Prostock-studio/Shutterstock


Previous studies have reported that maternal SARS-CoV-2 infections and immunological responses elevate the risk of altered fetal brain development, fetal death, growth restrictions and severe pathologies such as intraventricular hemorrhages and pneumonia. SARS-CoV-2 can reportedly infect developing human neurons within cerebral organoids. However, contrasting findings of greater SARS-CoV-2 presence in the choroid plexus of the organoids have also been reported.

About the study

In the present study, researchers assessed the effects of coronavirus disease 2019 (COVID-19) on fetal brain tissues.

The study was conducted between July 2020 and mid-April 2022 in the United Kingdom (UK), wherein human fetal tissues aged 9.0 to 21.0 pcw (post-conception weeks) were obtained from the HDBR (human development biology resource). In addition, lung specimens were obtained from SARS-CoV-2-positive individuals. Immunofluorescence and immunohistochemistry analyses were performed, and the immunostained sections were analyzed using confocal microscopy.

Further, ISH (in situ hybridization) analysis was performed using SARS-CoV-2 ribonucleic acid (RNA). Hemorrhages were quantified based on the number and size of erythrocyte clusters in the tissues. The team examined the number of hemorrhagic specimens associated with SARS-CoV-2 infection cases based on data sourced from the website.

To assess the chronicity of hemorrhages, the presence of ferric iron deposits that arise post-RBC lysis was examined with Prussian Blue staining. Next, the team examined the counts of cleaved caspase-3+ cells to determine whether the older or recent hemorrhages were related to increased cell deaths within cortical tissues. Furthermore, SARS-CoV-2 spike (S) protein expression was investigated in cells of the placenta, amnion, and umbilical cord.


A total of 661 specimens were obtained in 21.0 months, of which most were from elective terminations with no abnormalities documented. There were 62 specimens with chromosomal trisomy (44 specimens, 12 specimens, one specimen, one specimen, and three specimens with trisomy 21, trisomy 18, trisomy 16, trisomy 13, and triploid, respectively.

Cortical hemorrhage was observed among 26 specimens out of 661 fetal brain specimens. Only two similar cases with cortical hemorrhages were observed among 300 randomly chosen specimens out of 4,917 specimens sourced from the human development biology resource between September 1999 and December 2019. Therefore, the number of fetal specimens with cortical hemorrhages observed in the present study was unusual.

Among 26 hemorrhagic specimens examined, 25 no-abnormality specimens were obtained from elective terminations and one specimen had trisomy 21. SARS-CoV-2 presence was detected in the initial- and subsequent-trimester fetal brain associated with hemorrhage in the cortex. SARS-CoV-2 spike (S) expression was sparse in cortical microtubule-associated protein 2 (MAP2)-positive and HuC/D-positive neurons and the nestin-positive and Hopx (homeodomain-only protein)-positive radial glial, and Sox2 (sex-determining region Y-box 2)-positive ventricular zone and subventricular zone progenitor cells.

On the contrary, SARS-CoV-2 S was abundantly present within the choroid plexus of the cortical hemorrhage specimens.  In addition, SARS-CoV-2 was present sparsely in the placental, umbilical cord and amniotic tissues, indicating SARS-CoV-2 presence in maternal and fetal tissues. Cortical hemorrhages were associated with reduced integrity of blood vasculature and increased immunological cell infiltration in the fetal brain. 

The mean values of surface areas in the RBC clusters were 0.02 mm2 and 0.05 mm2 among non-hemorrhagic and hemorrhagic specimens, respectively, with the biggest cluster having a surface area of 1.3 mm2. In the cortical regions of the hemorrhagic specimens, blood vessels situated proximal to erythrocyte clusters showed significantly lower claudin-5 expression compared to away from vessels located far from the erythrocyte clusters.

Hemorrhagic specimens were obtained during periods corresponding to the highest COVID-19 case counts. The gestational stage in the hemorrhagic specimens varied between 8.0 pcw and 22 pcw, with most specimens (58%) obtained between 12.0 pcw and 14.0 pcw. Hemorrhagic specimens containing more erythrocyte clusters with none of the cells stained by the Prussian blue stain (indicating recent hemorrhage) comprised the least number of stained areas alone (indicating older hemorrhage), indicating that the specimens might denote different points in time from the hemorrhagic appearance.

The more recent hemorrhages were commonly observed among younger specimens (12.0 to 14.0 pcw) compared to older specimens (19.0 to 21.0 pcw). There were no statistically significant increases in caspase-3+ cells or cortical wall thickness among specimens with recent hemorrhages or older hemorrhages in comparison to the non-hemorrhagic specimens.

Elevated angiotensin-converting enzyme 2 (ACE2) expression was observed in the choroid plexus epithelium, and significant SARS-CoV-2 S and nucleocapsid (N) protein expression among all the five hemorrhagic specimens comprising the choroid plexuses (2.5-fold greater than background immunostaining), in comparison to specimens without hemorrhages, in aquaporin-1 positive cells. Low SARS-CoV-2 S expression was observed in one non-hemorrhagic specimen of the choroid plexus.

Overall, the study findings showed that SARS-CoV-2 infections could affect the fetal brain in the initial gestational period. In comparison to non-hemorrhagic specimens, those with cortical hemorrhages comprised erythrocyte clusters of significantly greater surface area, and significantly more erythrocyte clusters in every square mm of fetal tissue, with a significantly greater proportion of surface area in the cortical tissues comprising erythrocyte clusters. Further research must be conducted to assess the neurodevelopment sequelae of COVID-19. 

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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