Neonatal cerebral venous sinus thrombosis in the setting of maternal SARS-CoV-2 infection: Case report

Introduction

The highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19 disease, has infected more than 772 million people and resulted in more than 6 million deaths globally as of November 2023. ¹ Accordingly, infection of women during pregnancy has been widespread. The neurologic manifestations of COVID-19 have been described in the adult population. Additionally, the risks of cerebral venous sinus thrombosis (CVST) associated with COVID-19 and COVID-19 vaccination have been well established. ² However, very little is known about fetal exposure to maternal SARS-CoV-2 infection with respect to neurologic manifestations in general and CVST in particular.

The following case report describes a late preterm neonate who developed CVST born to a mother with severe SARS-CoV-2 and disseminated intravascular coagulation in the third trimester.

Case study

A 27-year–old, gravida 2 para 1, previously healthy mother presented with high fever, cough, and dyspnea during the 34th week of gestation. She tested positive for SARS-CoV-2 by PCR test and was managed conservatively as an outpatient. She then returned to hospital 2 days later due to decreased fetal movements. Prior to presentation to hospital, the pregnancy had been uncomplicated. Parents were nonconsanguineous. Routine ultrasounds were normal and serologies were protective. Mother was not vaccinated against COVID-19.

Fetal heart tracing showed minimal variability and decelerations leading to urgent Caesarean section at gestational age 35 weeks and 4 days. Following the delivery, the mother developed disseminated intravascular coagulation (DIC) requiring hospitalization until baby’s day of life (DOL) 3.

Baby was born flat with no respiratory effort and bradycardia (<100 bpm). APGARs were 1/10 at 1, 5, and 10 minutes. Neonatal resuscitation was started immediately with positive pressure ventilation, and baby was subsequently intubated at 10 minutes of life. She was hypotensive, requiring bolus of normal saline and dopamine infusion. The neonate was then transferred to our institution for further care. Venous cord gas at delivery had pH of 7.07 and base deficit of −14. PCR testing of nasopharyngeal swab for SARS-CoV-2 was negative.

Baby was cooled for a total of 3 days. Lip smacking movements were noted at 10 hours of life, so baby received 30 mg/kg of phenobarbital followed by an infusion of midazolam. Seizures recurred with attempts at weaning midazolam, requiring addition of levetiracetam and phenobarbital maintenance. Electroencephalography showed burst suppression pattern with short subclinical seizures of right centrotemporal onset. Magnetic resonance imaging (MRI) at day of life (DOL) 10 was suggestive of sinus venous thrombosis in the posterior part of the superior sagittal sinus as well as early venous ischemic changes in the parietal lobes bilaterally, and this was subsequently confirmed by MR venogram on DOL 19 (Figure 1). Hypercoagulable investigations demonstrated an elevated D-dimer >4000, aPTT 59, INR 1.5, and fibrinogen 2.4 on DOL2. Platelets were 275 on DOL2. There was no family history of venous thromboembolism. Baby was started on unfractionated heparin on day of life DOL 10 and subsequently changed to enoxaparin after 2 days due to heparin resistance.

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Figure 1.

Magnetic resonance imaging of the head with venogram demonstrating thrombus present in the posterior third of the superior sagittal sinus with (a) bilateral T2 hyperintensities most notable in the posterior quadrants. (b) demonstrates the phase contrast venogram in sagittal view, while (c) shows diffusion restriction from the venous infarct and (d) shows susceptibility weighted blooming artefact of hemorrhagic transformation.

Pathological examination of the placenta showed massive perivillous fibrin deposition, transmural type and focal chronic intervillositis. Fetal membranes with focal pigment-laden macrophages were seen consistent with meconium. Umbilical cord was normal.

Baby was discharged home on DOL 30 on levetiracetam, phenobarbital and enoxaparin. Follow up imaging at 3 months of age showed minimal residual thrombus in the posterior aspect of the superior sagittal sinus with preserved flow, and stable appearance of the parenchymal parieto-occipital injury. Serial clinical assessments have since been performed. At 17 months of life, she is seizure-free off antiseizure medication. She has vision and hearing deficits, but has begun to walk, use a few words, and is engaging in imaginative play.

Discussion

Neonatal CVST is a rare entity, and its diagnosis requires a high index of suspicion. Despite the prevalence of antepartum SARS-CoV-2 infection, the literature on neonatal outcomes of these pregnancies is limited. Vertical transmission has been documented, ³ but appears to be rare, with rates similar to those of other pathogens that cause congenital infection (e.g., pooled proportion of 3.2% in one systematic review ⁴ ). Transmission of SARS-CoV-2 to the neonate with associated encephalopathy, seizures, and stroke has been described.^5–8 However, even in the absence of direct transmission, maternal infection with SARS-CoV-2 may still have neurologic effects on the developing fetus. Maternal COVID-19 infection can also lead to placentitis, which may lead to severe placental damage, putting the fetus at risk for adverse neurological and systemic outcomes. ⁹

Inherited thrombophilia was considered on the differential diagnosis for this infant’s CVST. We did not perform extensive inherited thrombophilia testing as there was no suggestive family history, and because previous literature have demonstrated no significant role in extensive testing in neonatal stroke including testing for proteins C and S, antithrombin, factors VII/IX/XI, fibrinogen, lipoprotein(a), homocysteine, factor II G20210A (FII), and methylenetetrahydrofolate reductase C677T. ¹⁰ Accordingly, clinical guidelines for management of neonatal and perinatal stroke recommend extensive testing for inherited thrombophilias. ¹¹ At the time of clinic follow-up, there had been no further clinical concerns of thrombus.

One other case of a neonate with CVST born at 38 gestational weeks in the context of maternal COVID-19 infection in early third trimester has been reported, but the mother and infant tested negative by nasopharyngeal swab PCR testing. ¹⁰ No placental pathology or neonatal COVID serology was available in that report. Case reports have additionally documented neonates born to mothers with COVID-19 developing intraventricular hemorrhage, ¹¹ encephalopathy, ¹² seizures^12,13 and ventriculomegaly.^11,12 In a cohort of 21 SARS-CoV-2-positive pregnancies, the majority of newborns were asymptomatic, with only one infant presenting with perinatal asphyxia and seizures requiring resuscitation and therapeutic hypothermia. ¹³

The mechanisms by which maternal SARS-CoV-2 infection could lead to thrombosis in the fetus have not been fully elucidated. Thrombosis is likely to result from a combination of maternal as well as fetal/neonatal risk factors. The typical risk factors include preeclampsia, diabetes, perinatal hypoxic ischemia, traumatic delivery, and neonatal infection in addition to placental disorders and insult. ¹⁰ SARS-CoV-2 can be detected in placental tissue and in severe cases can lead to impairment of placental function. ¹³ Indeed, evaluation of placentas from women with COVID-19 during pregnancy show increased prevalence of decidual arteriopathy and other features of maternal vascular malperfusion relative to controls. Massive perivillous fibrin deposition (MPFD) has been strongly associated with COVID-19 infection in pregnancy, ¹⁴ and this was also noted in our case. We propose that the acute maternal COVID-19 infection in the present case may have caused or contributed to neonatal CVST through exacerbating existing hypercoagulability of pregnancy, and also through structural changes in the placenta.

MPFD is an uncommon placental finding associated with poor maternal and fetal outcomes, and this may recur in subsequent pregnancies. ¹⁵ The finding is characterized by a latticework of anastomosing bands of fibrin which demonstrates inappropriate activation of maternal coagulation pathways and fibrinoid extracellular matrix which is produced alongside an abnormal accumulation of intraplacental extravillous trophoblast. ¹⁶ In addition to maternal COVID-19, this finding is associated with pathophysiology of this finding has not been fully elucidated, but it is associated with maternal autoimmune disease, antiphospholipid antibody syndrome, or other acquired or genetic thrombophilic conditions. ¹⁷ In our case, there were no historical factors to support the latter items on the differential diagnosis for this placental finding.

Given the observational nature of our report, there are several limitations. Although neonatal CVST is relatively rare, with an estimated incidence of 1–12 in 100,000, ¹⁸ it is possible that maternal SARS-CoV-2 infection was coincidental and the neonate developed CVST due to another etiology or collection of risks. The pathological finding of MPFD could also be coincidental with SARS-CoV-2 infection, though no other historical feature of the mother puts her at risk of this placental finding.

Our study highlights the need for further research to clarify the effects of maternal SARS-CoV-2 infection on fetal thrombosis risk.^19,20