key: cord-0758039-4konugg2
authors: Magalhães, João Eudes; Sampaio‐Rocha‐Filho, Pedro Augusto
title: Pregnancy and neurologic complications of COVID‐19: A scoping review
date: 2022-04-07
journal: Acta Neurol Scand
DOI: 10.1111/ane.13621
sha: 846b0f5dd56aabf90fe83a66d0511d070ead2113
doc_id: 758039
cord_uid: 4konugg2

While neurologic complications are frequently reported among patients with COVID‐19 in the general population, they are unknown in pregnant women. This paper summarizes the case reports of pregnant women with confirmed SARS‐CoV‐2 infection plus a specified neurologic diagnosis. Until November 2021, 18 case reports were found. Both the central and peripheral nervous systems were equally affected: delirium (n = 1), posterior reversible encephalopathy syndrome (n = 4), cerebrovascular disease (n = 2), acute cerebral demyelinating disease (n = 1), acute necrotizing encephalopathy (n = 1), Guillain–Barré syndrome (n = 5), including one patient who also had vestibular neuritis, Bell's palsy (n = 3), and rhabdomyolysis (n = 1). The median maternal age was 32.5 (25—35) years, the median gestational age was 34 (30—36.5) weeks, and 38.9% presented previous medical conditions. Respiratory symptoms were reported in 76.5%, and 76.5% received immunotherapies to treat the COVID‐19 or the neurologic complications. Half the women required admission to ICU and, more often, were those with central nervous system involvement (77.8% vs. 22.2%; Chi‐square test, p = .018). For 64.7% of women, the most common method of delivery was surgical, although just one case was due to the neurologic complication. There were reports of one spontaneous abortion, two fetal deaths, and no maternal deaths. Only one case presented a poor neurologic outcome. It is possible that our findings are underestimated, considering that there are thousands of reports regarding neurologic complications in the general population with COVID‐19.

is much more frequently associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. 7 Neurologic symptoms, such as fatigue and headache, are among the most common presenting symptoms of COVID-19. [8] [9] [10] [11] Moreover, anosmia and ageusia are the most specific neurologic manifestations for diagnosing COVID-19, although they present a low sensitivity. 12 Besides being prevalent and affecting almost half the patients with COVID-19, 13 neurologic complaints may be a warning sign of several neurologic complications.

Although relatively rare in previously reported coronaviruses, there have been frequent reports of both central and peripheral nervous system involvement among patients with COVID-19. 14, 15 Encephalopathy, Guillain-Barré syndrome (GBS), and stroke are the most common neurologic conditions reported in association with 11, 15 Delirium, as a presenting feature of encephalopathy, and stroke have been associated with severe COVID-19. 11, 16, 17 During pregnancy, the innate and adaptive immune responses shift from an inflammatory phenotype to an anti-inflammatory phenotype. 18 Moreover, physiological and immunomodulatory changes during pregnancy may exacerbate the presentation of COVID- 19, 2 and the neuroinvasive propensity of coronaviruses may be magnified by the physiologic susceptibility of pregnancy. 19 However, we found no specific reviews regarding neurologic complications in pregnant women with COVID-19.

In this scoping review, we consider which neurologic complications of COVID-19 have been reported during pregnancy and postpartum and have summarized the evidence to date for complicated COVID-19 in women during the peripartum period. We have also examined the reported putative mechanisms of COVID-19-associated neurologic disease in this subgroup of patients.

A search was undertaken of PubMed/MEDLINE, Cochrane Library, LILACS, and SciELO databases for articles on COVID-19 from inception to November 25, 2021 , with no language restrictions, using the terms "COVID-19," "novel coronavirus," "SARS-CoV-2," or "coronavirus" and "pregnancy," "pregnant women," or "postpartum period" in combination with "neurological," "nervous system," "encephalitis," "encephalopathy," "seizure," "ataxia," "myelopathy," "Guillain-Barré syndrome," "myopathy," "rhabdomyolysis," "peripheral neuropathy," "neuritis," "cerebrovascular," "stroke," "cerebral venous sinus thrombosis," "neuromuscular," or "brain."

The references of the selected studies were also reviewed for additional articles. Publications with a precise neurologic diagnosis were included, especially those with extensively investigated neurologic manifestations, and ranged from case reports to cases included in case series, with a confirmed diagnosis of COVID-19 based on either a real-time polymerase chain reaction (RT-PCR) or SARS-CoV-2 antibodies. Publications were excluded with strictly psychiatric presentations with no evidence of neurologic disease or cases with isolated neurologic symptoms or neurologic disease not directly associated with COVID-19.

From the selected case reports, we registered the following: the month of publication; the clinical presentation data (maternal and gestational age, previous gestational history and complications in the current gestation, initial respiratory or neurologic symptoms, and neurologic examination): the detection method of SARS-CoV-2, plus blood tests and radiology findings; the neurologic investigations (brain or spinal cord images, angiographic studies, cerebrospinal fluid analysis, electroencephalogram, nerve conduction study, and needle electromyography); COVID-19, obstetric and neurologic management; findings on disease progression during follow-up; COVID-19, obstetric, fetal and maternal neurologic outcomes; and diagnosis of the neurologic condition.

A total of 80 articles were found, and 14 publications were selected, to which we added three published reports found in the references of these selected articles. Finally, we reviewed 18 case reports from the selected 17 papers (Tables 1 and 2 ). [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] Nine women (50%) presented with central nervous system (CNS) involvement. There were no cases with both CNS and peripheral nervous system (PNS) involvement at the same time. The overall maternal age ranged from 19 to 40 years for the 18 women, with a median age of 32.5 (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) years. The gestational age ranged from 12 to 40 weeks in 16 of the reported cases, with a median age of 34 (30-36.5) weeks. Seven out of 18 women (38.9%) presented at least one previous medical condition.

Thirteen out of 17 women (76.5%) reported some respiratory symptom. All cases with reported data presented abnormalities in the blood tests (n = 15) and chest images (n = 10); these findings were associated with COVID-19 in all cases. The median maternal age, median gestational age, and previous medical condition or respiratory symptoms were similar to patients with CNS and PNS involvement. In addition, we were unable to find the COVID-19 vaccination status for any of the reported cases. The most common method of delivery was cesarian section; in 11 out of 17 cases (64.7%), seven were due to fetal distress associated with a worsening maternal respiratory status, three due to obstetric indications (two cases of suspected preeclampsia, and one twin pregnancy with rupture of membranes), and one due to increased intracranial pressure associated with cerebral venous sinus thrombosis (CVST). There was no difference in the frequency of cesarian section when comparing CNS or PNS involvement.

Only one out of 18 women (5.6%) presented a poor neurologic outcome and remained with disabilities related to a diagnosis of Guillain-Barré syndrome. There were no maternal deaths. Three out of 13 cases (23.1%) presented a poor fetal outcome, one spontaneous abortion at 12 weeks of gestation, and two fetal deaths possibly due to prematurity. No association was observed between the clinical parameters and maternal or newborn outcomes.

Central nervous system involvement was reported in nine cases [20] [21] [22] [23] [24] [25] [26] [27] [28] ( Table 1) : delirium 20 (n = 1); posterior reversible encephalopathy syndrome [21] [22] [23] [24] (PRES) (n = 4); cerebrovascular disease 25, 26 (CVD) (n = 2), one case of arterial involvement and one of venous; acute cerebral demyelinating disease 27 (ADEM) (n = 1); and acute necrotizing encephalopathy 28 (ANE) (n = 1).

Among the five cases presenting with encephalopathy (delirium and PRES), four patients presented with altered behavior and mental status or impaired consciousness [20] [21] [22] 24 ; three with headache 20, 21, 24 ; three with generalized seizures 21, 23, 24 ; and one patient with bilateral blindness. 23 All these findings indicate diffuse brain injury, and one case also presented with signs of focal brain deficit: hemiparesis and aphasia. 22 While none of the four cases of PRES had previously been diagnosed with chronic hypertension, they all presented episodes of hypertension. [21] [22] [23] [24] Notwithstanding, in just one case report of PRES there was reference to a suspicion of preeclampsia, although this woman showed no brain CT scan abnormality. 23 All the other three cases of PRES presented abnormalities in the brain MRI, including two cases of asymmetrical lesions, one with posterior predominance 21 and one with anterior, 22 and there was also one case of symmetrical, posterior lesions with an atypical finding of hemorrhages. 24 One case also demonstrated leptomeningeal enhancement, suggesting a slow blood flow. 22 Only one case repeated the brain MRI, which revealed a complete reversion of the lesions. 21 None of these three cases were diagnosed with preeclampsia. The only woman diagnosed with delirium was also diagnosed with preeclampsia and presented a normal brain CT scan. 20 Angiographic studies were undertaken in three cases of PRES, which demonstrated no abnormalities. [22] [23] [24] The CSF analysis on one woman with PRES revealed elevated protein levels with no signs of infection. 24 Both women with cerebrovascular disease presented with headaches and signs of focal brain lesions, including, in both cases, unilateral motor signs, 25, 26 hemianopsia, 25 or aphasia. 26 The women diagnosed with ischemic stroke also presented focal seizures; the brain image revealed an extensive infarct with a hemorrhagic component and a possible lesion in the related arterial trunk. 25 The brain image of the other case also presented an infarct associated with extensive venous thrombosis, and she went on to develop increased intracranial pressure. 26 Two women were diagnosed with inflammatory brain diseases: the first patient was diagnosed with ADEM due to tetraparesis, noted after an improvement of the critical status during the fourth week of COVID-19. Images revealed bilateral, asymmetric cerebral lesions suggestive of brain demyelination and no spinal cord lesions, and the CSF analysis ruled out infection with a negative test for SARS-CoV-2. 27 The second patient with ANE, after 1 week of respiratory symptoms, presented with mental confusion, aphasia, and paresis of the right arm. Images revealed bilateral, symmetric lesions suggestive of brain inflammation with bleeding and no vascular involvement. 28 A CSF tap was not undertaken in this last case due to the risk of complications. Both women presented good outcomes.

Peripheral nervous system involvement was reported in nine cases 19, [29] [30] [31] [32] [33] [34] [35] (Table 2) : GBS 29-33 (n = 5), among which, one case also presented vestibular neuritis 33 ; Bell's palsy 19, 29, 34 (n = 3); and rhabdomyolysis 35 (n = 1).

The first symptoms of GBS developed during the first week of COVID-19 in three cases [30] [31] [32] and after the first month in 2 cases. 29, 33 One patient was diagnosed with GBS with no further investigations, 29 while all the other four cases had been investigated. These last cases presented with sensory complaints, including low back pain 30 and distal paraesthesia. [30] [31] [32] [33] Three patients also reported a decreased sensation with no sensory level. [31] [32] [33] All four cases presented motor impairment, including unilateral 30 or bilateral 31-33 facial paresis; ascending tetraparesis [30] [31] [32] ; and areflexia. [30] [31] [32] [33] Two women presented manifestations of dysautonomia, including hypertension, 31 dysphonia, 31 dysphagia, 30, 31 or dyspnea. 30 Two cases had undergone brain and spinal cord imaging exams, which proved to be unremarkable. 32 One case with GBS also presented unilateral findings of hearing loss and vestibular impairment, including fullness of the ear, tinnitus, vertigo, and nystagmus, which was confirmed by otoneurologic tests and videonystagmography. 33 Bell's palsy was diagnosed in three patients with no further investigations being conducted. 19, 29, 34 Anosmia and dysgeusia were reported by one woman, along with fever and generalized weakness. 34 Just one case was diagnosed with rhabdomyolysis based on laboratory findings after a long, complicated period in ICU. However, no further investigations were carried out to rule out neuropathy or myopathy. 35 

In this scoping review, we found few case reports of neurologic complications of COVID-19 in women during pregnancy or the postpartum period, considering that until June 2020 there were more than ten thousand patients reported with neurologic involvement in the general population with COVID-19. 15 Neurologic signs and symptoms are more prevalent than specific neurologic conditions in the general population with COVID-19

(86.3% and 13.7%, respectively), and these complications are more common in the inpatient setting. 15 mainly because most of them are either asymptomatic or they present with mild respiratory symptoms, 5 and also because they are younger and have fewer comorbidities than non-pregnant women. 6 Although pregnant women have a higher risk for mechanical ventilation and the need for ICU than non-pregnant women, outcomes and mortality of COVID-19 appear to be no different in pregnant women. 6, 37 However, the risk of surgical delivery and preterm birth was higher among pregnant women with COVID-19 compared with the general pregnant population. 37 In our review, CNS involvement was associated with ICU admission, but overall, outcomes were good, and the method of delivery was chosen due to the neurologic complication in just one patient. We found no research regarding neurologic complications and pregnancy outcomes in COVID-19

patients. Guillain-Barré syndrome in PNS involvement. 15 These were also the most common conditions in the cases summarized in our review.

Encephalopathy may be the predominant disorder in the initial presentation of COVID-19. 11, 15 Many patients had no brain imaging findings or presented with PRES or features of hemorrhagic necrotizing encephalopathy. 15 One of the reported cases of pregnant women with COVID-19 presented with delirium with no evident brain injury. 20 There were also four cases of PRES, [21] [22] [23] [24] and only one of these women presented no abnormalities in the brain image. 23 The cause of delirium is usually multifactorial, including a stress response to infection or physical and psychiatric modifications linked to pregnancy and puerperium. However, it has become a rare disorder because of current perinatal care. 20 Moreover, delirium may be the presenting feature of PRES, a condition that disrupts autoregulatory brain vascular mechanisms due to the direct or indirect effects of SARS-CoV-2 over the brain endothelium. [21] [22] [23] [24] Posterior reversible encephalopathy syndrome is usually linked to preeclampsia, which is approximately twice as frequent in COVID-19 pregnant women, even those who have no respiratory symptoms. 7 Interestingly, only one of the four reported cases of PRES presented suspected preeclampsia, 23 although all of them presented episodes of hypertension. [21] [22] [23] [24] The women with delirium were also diagnosed with preeclampsia. 20 Acute cerebral demyelinating disease is a rare, immune-mediated syndrome of multifocal demyelination of the CNS that typically occurs weeks after a viral infection in children and presents with acute encephalopathy and multiple focal neurologic signs and symptoms. 27 Until November 2020, there were 760 stroke cases among patients with COVID-19, of which most were ischemic strokes. 40 In this study, the estimated prevalence was 1.11% (1.03%-1.22%) for ischemic stroke and 0.46% (0.40%-0.53%) for hemorrhagic stroke.

Commonly, older men with hypertension, hyperlipidemia, and diabetes mellitus were affected with stroke as a complication of COVID-19, and their mean National Institutes of Health Stroke Scales (NIHSS) scores were high. 40 At least two-thirds presented respiratory symptoms, and their common stroke indicatives were unilateral motor deficits (67%), altered consciousness (66%), and headache (11%). 41 Admission to ICU, ventilatory assistance, and mortality rates were higher for COVID-19 patients who suffered any type of stroke. [40] [41] [42] The outcomes were better for young patients in the fifth decade of life and poor in severe COVID-19 cases. 41 Although the only pregnant woman with an ischemic stroke presented a severe form of COVID-19, her outcome was good possibly because she was young and had no previous medical conditions. 25 [30] [31] [32] [33] Until January 2021, there were 56 patients reported with COVID-19 and cranial nerve involvement, of which two-thirds were isolated cranial neuropathies. 45 Except for trochlear and accessory nerves, all other cranial neuropathies were described in patients with COVID-19, most with unilateral involvement of the facial nerve, oculomotor nerves (III and VI), or the optic nerve. 45 The three cases of cranial nerve involvement in pregnant women were classified as 

Bell's palsy and were all unilateral. 19, 29, 34 The only case of vestibular neuropathy was associated with GBS. 33 Cranial neuropathies in patients with COVID-19 were often associated with GBS, 44, 45 and bilateral cranial nerve involvement in COVID-19 was also commonly associated with GBS. 45 Muscle injury due to COVID-19 may manifest as an asymptomatic elevation of creatine kinase to severe rhabdomyolysis. This is possibly due to myositis, which can cause myoglobinuria and acute kidney disease. Patients may present with generalized weakness.

There are a few individual case reports of rhabdomyolysis associated with COVID-19, 46 including one case in a critically ill patient similar to the pregnant women reported. 35 49 Infection with the influenza virus may cause encephalopathy, encephalitis, and GBS and tend to affect children more often. 48 We found no cases of neu- 

Pathophysiologically, it is possible that SARS-CoV-2 directly infects the brain through nasal epithelial cells or brain endothelium, given the prevalence of ACE2 expression in both locations. 36 Moreover, neurologic complications of COVID-19 may also be due to the secondary effects of infection, including hypoxia, drugs, toxins, metabolic derangements, 38 or hyperimmune responses, often referred to as "cytokine storm." 36 The detection rate of SARS-CoV-2 RNA and proteins in brain specimens is not related to neurologic symptoms, and inflammatory infiltrates are more frequently associated with neurologic impairment. 51 Therefore, immune responses may be an essential pathophysiological factor for brain injury, causing encephalopathies and encephalitis in COVID-19 patients, especially those who become severely ill. It is thought that the proinflammatory state induced by the cytokine storm may be responsible for glial cell activation and the subsequent demyelination. 27 SARS-CoV-2 has a high affinity for ACE2 receptors expressed by endothelial cells and arterial smooth muscle cells throughout the body, including the brain. 25, 36 Inflammation, platelet activation, endothelial dysfunction, and blood flow stasis associated with COVID-19 predispose patients to thrombotic events, mainly associated with the transient prothrombotic state of pregnancy and puerperal period. 26 The binding of SARS-CoV-2 to ACE2 also impairs the conversion of angiotensin II, which has vasoconstrictive and proinflammatory effects. It is possible that this is the way in which COVID-19 increases the risk of vasomotor dysfunction related to preeclampsia, 7 as well as other vascular complications.

In the few case reports summarized in this scoping review, none of them used standard guidelines to report scientific data, such as CARE guidelines. Thus, essential information may be lacking. Furthermore, it seems evident that neurologic complications were underestimated during the COVID-19 pandemic among pregnant women. Therefore, a significant proportion of young and previously healthy pregnant women may have progressed with non-severe COVID-19, leading to mild neurological manifestations and complications. In addition, the overlapping of preeclampsia and eclampsia features could have contributed to low identification rates of specific neurologic conditions.

It was only possible to find 18 case reports of pregnant women with both COVID-19 and a neurologic complication published until November 2021 and was possibly underestimated. The central nervous system and the peripheral nervous system were equally affected, but acute respiratory distress syndrome due to COVID-19

and ICU admission were more frequent among women with central nervous system conditions. Only one case presented a poor neurologic outcome.

The authors report no conflict of interest.

JEM and PASRF contributed to conception and study design; acquisition and analysis of data; and drafting of the manuscript and tables.

The peer review history for this article is available at https://publo ns.com/publo n/10.1111/ane.13621.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

João Eudes Magalhães https://orcid.org/0000-0001-5523-1760

Pedro Augusto Sampaio-Rocha-Filho https://orcid. org/0000-0001-5725-2637

World Health Organization

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