Letter to the Editor Regarding ‘A neonatal case of cerebral venous sinus thrombosis with intrauterine onset after COVID19 infection during pregnancy: cause or coincidence?’

We read with interest the article by Ozdil et al. about a three day-old female neonate who was diagnosed with venous sinus thrombosis (VST) which was complicated by a subacute, partial ischemic stroke in the territory of the right middle cerebral artery.¹ The age of the stroke was estimated at 14-28 days before birth.¹ Because the mother suffered a mild coronvirus disease-19 (COVID-19) infection during the initial weeks of the third trimester (gestational weeks 27-30), VST in the fetus was causally related to the severe, acute respiratory syndrome-coronavirus type-2 (SARS-CoV-2) infection of the mother.¹ The study is appealing but carries limitations that raise concerns and should be discussed.

The assumption of a causal connection between the COVID-19 infection2 of the mother in the “initial weeks of the third trimester” and the VST in the fetus remains unproven. There are several arguments against a causal relationship. First, the fetus or neonate was never confirmed to have a SARS-CoV-2 infection. The nasopharyngeal swab test was negative in the neonate and anti-SARS-CoV-2 antibodies were not determined. Furthermore, it is generally unproven that there is an intrauterine or transplacentar transmission of the SARS-CoV-2 virus.² Second, the latency between maternal COVID-19 infection and development of VST is presumably >4 weeks. To clarify the duration of the latency it should be specified during which gestational weeks the mother suffered from COVID-19. Assuming that the COVID-19 infection occurred between gestational weeks 27 and 30 and that VST in the fetus occurred between gestational weeks 37 and 38, the latency is at least six weeks, making a causal relation quite unlikely. Third, differential causes of fetal VST were not appropriately ruled out. These include trauma, thrombophilia, dural sinus malformation, and hemangioma.³

The term “chronic ischemic hemorrhage” used in the legend of figure 1 by Izdil et al. is not understandable. Do the authors mean that there was an ischemic stroke with secondary bleeding or do they mean that there was primary bleeding? According to the images shown in figure 1 the patient had an acute ischemic lesion.¹ To document bleeding it would be necessary to know if there was a hypointensity on susceptibility weighted images (SWI) or a hyperdensity on cerebral computed tomography (CCT).

A limitation of the study is that xantochromia was not explained. The most common causes of xanthochromia are subarachnoid bleeding, hematomyelia, tuberculous meningitis, excessive increase in cerebrospinal fluid (CSF) protein, or fulminant icterus. We should know if all these differential causes were thoroughly ruled out.

Further limitations are that cytokines, chemokines, and glial factors were not determined in the neonate's CSF and that no reference limits for blood chemical values were provided, making interpretation of the reported values difficult. Cytokines and chemokines are commonly elevated in case of cerebrospinal fluid/peripherall nervous system (CNS/PNS) involvement of a SARS-CoV-2 infection.⁴

Overall, the interesting study has limitations that call the results and their interpretation into question. Clarifying these weaknesses would strengthen the conclusions and could improve the study. Before attributing fetal VST to a SARS-CoV-2 infection of the mother, transmigration of the virus from the mother to the fetus or induction of a cytokine storm in the fetus should be demonstrated.

Funding

No funding was received.

Data access statement

All data are available from the corresponding author.

Ethics statement

Not applicable.

Author contribution

JF: design, literature search, discussion, first draft, critical comments, final approval.

Data access statement: not applicable

Compliance with Ethics Guidelines: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Declaration of Competing Interest

Disclosures: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.