Effects of coronavirus disease 2019 vaccination on seizures in patients with epilepsy : Chinese Medical Journal

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Original Article

Effects of coronavirus disease 2019 vaccination on seizures in patients with epilepsy

Fang, Xiqin1,2; Qiao, Shan2,3; Zhang, Ranran1,2; Yang, Tingting1,2; Wang, Zhihao1,2; Kong, Qingxia4; Sun, Meihua5; Geng, Jianhong6; Fang, Chunyan7; Chen, Yanxiu8; Sun, Yanping9; Zhang, Dongmei10; Qu, Lixing11; Shang, Wei12; Wang, Jianguo13; Liu, Xuewu1,2

Editor(s): Wei, Peifang; Pan, Xiangxiang

Author Information
Chinese Medical Journal ():10.1097/CM9.0000000000002558, February 28, 2023. | DOI: 10.1097/CM9.0000000000002558



Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to various clinical outcomes, ranging from asymptomatic infection to severe acute respiratory distress and death.[1] According to relevant data, more than 639 million patients had been diagnosed with COVID-19 worldwide by the end of November 2022. An ideal solution to end this pandemic is by administering safe and effective vaccines. With the disclosure of the viral genome in January 2020,[2] the development of various vaccines has been initiated.

Patients with epilepsy (PWE) are a special group, and vaccination may have a certain impact on their condition. Recent studies have indicated that diphtheria, tetanus, and pertussis (DTP) and measles, mumps, and rubella (MMR) vaccines are the two vaccinations that can significantly increase the risk of febrile convulsions and seizures.[3,4]

Furthermore, several currently approved COVID-19 vaccines in the market have been associated with many adverse reactions, including severe neurological adverse reactions such as transverse myelitis.[5] This has motivated neurologists and PWE to consider whether PWE should be vaccinated against COVID-19. According to a study, most of the neurologists may recommend vaccination for PWE only if the COVID-19 vaccine is safe and reliable.[6] Another study revealed that approximately one-third of PWE were unwilling to receive the COVID-19 vaccine because of fear of worsening their seizures.[7] Neurologists and PWE are concerned that vaccination may increase the risk of seizures. In addition, they are concerned that PWE may not be protected by vaccines, making them remain susceptible to SARS-CoV-2 infection. However, because studies have demonstrated that the COVID-19 pandemic may worsen the physical and psychological conditions of PWE, eventually resulting in seizure aggravation,[8,9] COVID-19 vaccination seems to be imperative for PWE. To sum up, clinical evidence of the risk of seizures in PWE after COVID-19 vaccination is critical to helping PWE for taking decisions on the vaccination. Therefore, we designed this multicenter retrospective study to evaluate the impact of COVID-19 vaccination on seizures in PWE, aiming to provide a reference for neurologists and PWE.


Ethical approval

The study was approved by the Medical Ethics Committee of Qilu Hospital of Shandong University (No. 2021035). All patients or their guardians who agreed to participate in this study signed an informed consent form.

Patients and study design

According to the diagnostic criteria proposed by the International League Against Epilepsy (ILAE) in 2017, PWE, who received COVID-19 vaccination (regardless of vaccine type), were retrospectively and consecutively included from the epilepsy centers of 11 hospitals in China from May 1, 2021 to September 1, 2021 [Supplementary Table 1, https://links.lww.com/CM9/B401]. The patients were divided into two groups based on the recurrence of seizures within 14 days after vaccination. Patients who experienced seizures were assigned to the SAV (seizures after vaccination) group, while the remaining patients were assigned to the SFAV (seizure-free after vaccination) group. The currently available COVID-19 vaccines in China mainly include those from “Sinopharm” (Beijing, China; inactivated vaccine, two doses) and “Sinovac” (Beijing, China; inactivated vaccine, two doses). No restrictions were imposed on the type of COVID-19 vaccine received by the patients; patients who provided informed consent and completed the questionnaire were included in this study. Patients who were vaccinated <14 days were followed up by telephone interview to complete the questionnaire. Patients or their guardians, who refused to provide informed consent, those who did not cooperate with completing the questionnaire or follow-up, those who could not provide an accurate history of seizures (including before and after vaccination), and those who were lost to follow-up, were excluded from the study. In addition, we retrospectively included outpatients with epilepsy who had not been vaccinated against COVID-19 and had discontinued or reduced their medication as controls from Qilu Hospital of Shandong University from June 1, 2021 to May 1, 2022.

Collection of data from patients

For PWE who had been vaccinated against COVID-19, in addition to basic and related information regarding vaccination, the questionnaire addressed the status of epilepsy control before vaccination, seizure type, cause of epilepsy, anti-seizure medications (ASMs) taken and their adverse reactions, results of the most recent electroencephalogram (EEG) before vaccination, seizures within 14 days after vaccination, medication after vaccination, and adverse reactions to vaccination and their severity. Patients were divided into five categories based on the duration of seizure freedom before vaccination as follows: <3 months (Grade I); ≥3 to 6 months (Grade II); >6 months to 1 year (Grade III); >1 year to 2 years (Grade IV); and >2 years (Grade V). According to the ILAE 2017 standard, seizure types were classified into three categories: focal, generalized, and unknown onset. For PWE who had not been vaccinated against COVID-19 and had discontinued or reduced their medication, the information collected included age, sex, seizure type, cause of epilepsy, number of ASMs taken, duration of seizure freedom before withdrawal from or reduction in ASMs and the status of seizure after withdrawal from or reduction in ASMs.

Primary and secondary observation indicator

Previous studies have reported an increased risk for febrile convulsions or seizures within 2 weeks of vaccination.[10-14] Therefore, the primary indicator for observation was whether patients experienced seizures within 14 days after vaccination (patients who were vaccinated with multidose vaccines, were assigned to the SAV group if they experienced seizures within 14 days after any dose). Based on this criterion, the peri-vaccination period was defined as 14 days before and after any vaccine dose. Secondary observation indicators included frequency, severity of non-epileptic adverse events, and occurrence of status epilepticus after vaccination.

Statistical analysis

The Chi-squared test or Fisher's exact test was used to analyze the differences in categorical variables between two groups. The Shapiro-Wilk test was employed to determine whether the continuous variable conformed to normal distribution. The independent-samples t-test was used for analyzing continuous variables conforming to normal distribution, and the Mann-Whitney U test was used for analyzing ranking variables and continuous variables that did not conform to normal distribution. To determine the risk factors of seizure recurrence after vaccination, binary logistic regression analysis was performed. PWE with or without vaccination but had the behavior of drug reduction or withdrawal were divided into two groups according to recurrence or not, and binary logistic regression analysis was performed to determine whether vaccination would affect the recurrence rate of PWE who had drug reduction or withdrawal. A P value <0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences (version 26, International Business Machines Corporation, Armonk, New York, USA).


Demographic characteristics

We selected a total of 445 patients; of which, 38 were excluded owing to the following reasons: (1) inability to complete the questionnaire or follow-up; (2) inability to provide accurate seizure information. Eventually, data from 407 patients were included and used for further analyses. Furthermore, 48 (11.8%) patients were assigned to the SAV group, whereas the remaining 359 (88.2%) patients were assigned to the SFAV group.

The age range of patients was 10 to 80 years, consisting of 229 (56.3%) men and 178 (43.7%) women. In addition, 117 (28.7%) patients had a clear cause of epilepsy, and 54 (13.3%) patients discontinued ASMs or reduced their dosage during the peri-vaccination period (ASM reduction was mainly due to spontaneous missed medication in PWE, while withdrawal mainly occurred in PWE with well-controlled seizures under medical advice). A total of 70 (17.2%), 56 (13.8%), 56 (13.8%), 70 (17.2%), and 155 (38.1%) patients had seizure freedom Grades I, II, III, IV and V, respectively. The most frequent type of seizure (309, 75.9%) was a focal seizure (with or without impaired awareness). Common ASMs included valproate (123, 30.2%), oxcarbazepine (114, 28.0%), levetiracetam (100, 24.6%), carbamazepine (76, 18.7%), lamotrigine (49, 12.0%), topiramate (22, 5.4%), lacosamide (26, 6.4%), and perampanel (17, 4.2%). Moreover, 43 (10.6%), 219 (53.8%), 112 (27.5%), and 33 (8.1%) patients were taking 0, 1, 2, or >2 types of ASMs, respectively. Twenty of 337 (5.9%) patients, who were seizure-free for >3 months before vaccination, experienced seizures after vaccination, while the proportion was 40.0% (28/70) in patients with seizures within 3 months before vaccination. Seizures occurred in 25.9% (14/54) of patients who discontinued ASMs or reduced their dosage compared with 9.6% (34/353) of patients who refrained from doing such.

Univariate analysis

Univariate analysis of the above-mentioned factors revealed that withdrawal from or reduction of ASM (P = 0.002), the duration of seizure freedom (P < 0.001), and taking levetiracetam (P = 0.009) were significantly different between the two groups [Table 1].

Table 1 - Basic characteristics of PWE with or without the seizure within 14 days after COVID-2019 vaccination.
Variables SAV (n = 48) SFAV (n = 359) Z/χ 2 P value
Age −0.728 0.467
 <18 years 3 (6.3) 31 (8.6)
 ≥18 and ≤30 years 20 (41.7) 158 (44.0)
 >30 and ≤40 years 11 (22.9) 86 (24.0)
 >40 and ≤50 years 10 (20.8) 45 (12.5)
 >50 and ≤60 years 2 (4.2) 26 (7.2)
 >60 years 2 (4.2) 13 (3.6)
Male 29 (60.4) 200 (55.7) 0.381 0.323
Epileptic etiology 0.886
 Unknown 34 (70.8) 256 (71.3)
 Trauma 5 (10.4) 47 (13.1)
 Heredity 5 (10.4) 24 (6.7)
 Inflammation 1 (2.1) 12 (3.3)
 Tumor 1 (2.1) 5 (1.4)
 Vascular 2 (4.2) 12 (3.3)
 Metabolism 0 (0) 3 (0.8)
Withdrawal from or reduction of ASM 14 (29.2) 40 (11.1) 11.953 0.002
Duration of seizure freedom −6.032 <0.001
 Grade I 28 (58.3) 42 (11.7)
 Grade II 6 (12.5) 50 (13.9)
 Grade III 3 (6.3) 53 (14.8)
 Grade IV 3 (6.3) 67 (18.7)
 Grade V 8 (16.7) 147 (40.9)
Seizure type 0.210 >0.999
 Focal 35 (83.3) 274 (76.3)
 Generalized 7 (14.6) 43 (12.0)
 Unknown 6 (12.5) 42 (11.7)
Use of ASM
 Valproate 16 (33.3) 107 (29.8) 0.250 0.364
 Carbamazepine 11 (22.9) 65 (18.1) 0.645 0.266
 Oxcarbazepine 14 (29.2) 100 (27.9) 0.036 0.485
 Levetiracetam 5 (10.4) 95 (26.5) 5.882 0.009
 Lamotrigine 2 (4.2) 47 (13.1) 3.182 0.050
 Topiramate 3 (6.3) 19 (5.3) 0.493
 Perampanel 4 (8.3) 13 (3.6) 0.128
 Lacosamide 5 (10.4) 21 (5.8) 0.179
Number of ASMs −0.103 0.918
 None 11 (22.9) 32 (8.9)
 1 17 (35.4) 202 (56.3)
 2 13 (27.1) 99 (27.6)
 ≥3 7 (14.6) 26 (7.2)
Data are presented as count (percentage).
Z values.
χ2 values.
Fisher's exact test. ASM: Anti-seizure medication; COVID-19: Coronavirus disease 2019; PWE: Patients with epilepsy; SAV: Seizures after vaccination; SFAV: Seizure-free after vaccination; –: Not available.

Binary logistic regression analysis

Factors in the univariate analysis were included in binary logistic regression analysis. The results revealed that seizures occurring within 3 months before vaccination and withdrawal from or reduction of ASMs during the peri-vaccination period (odds ratio [OR] = 7.384, 95% confidence interval [CI] = [1.732–31.488], P = 0.007) were significantly associated with the recurrence of seizures [Table 2].

Table 2 - Analysis of risk factors for recurrence of seizures within 14 days after COVID-2019 vaccination in PWE by binary logistic regression.
Variables OR 95% CI P values
Duration of seizure freedom
 Grade I
 Grade II 0.163 0.053–0.502 0.002
 Grade III 0.453 0.090–2.281 0.337
 Grade IV 0.942 0.161–5.522 0.947
 Grade V 1.265 0.303–5.286 0.747
Withdrawal from or reduction of ASM
 No Ref
 Yes 7.384 1.732–31.488 0.007
 No Ref
 Yes 0.306 0.043–2.188 0.238
 No Ref
 Yes 0.248 0.044–1.416 0.117
Number of ASMs
 0 Ref
 1 1.784 0.229–13.869 0.580
 2 3.218 0.159–65.069 0.446
 ≥3 11.257 0.148–858.494 0.274
 <18 years Ref
 ≥18 and ≤30 years 0.615 0.127–2.988 0.547
 >30 and ≤40 years 0.812 0.313–2.108 0.669
 >40 and ≤50 years 1.334 0.423–4.208 0.623
 >50 and ≤60 years 0.322 0.059–1.775 0.193
 >60 years 0.977 0.155–6.162 0.981
 Male Ref
 Female 0.653 0.292–1.460 0.299
Epileptic etiology
 Unknown Ref
 Trauma 0.526 0.158–0.752 0.295
 Heredity 1.900 0.502–7.184 0.344
 Inflammation 0.730 0.053–10.061 0.814
 Tumor 1.631 0.087–30.716 0.744
 Vascular 1.236 0.171–8.924 0.834
 Metabolism 0.999
Seizure type
 Focal Ref
 Generalized 0.801 0.256–2.508 0.703
 Unknown 0.694 0.608–7.120 0.759
 No Ref
 Yes 0.601 0.106–3.397 0.565
 No Ref
 Yes 0.966 0.197–4.737 0.966
 No Ref
 Yes 0.863 0.184–4.038 0.851
 No Ref
 Yes 0.519 0.051–5.279 0.580
 No Ref
 Yes 1.211 0.177–8.269 0.845
 No Ref
 Yes 0.646 0.095–4.369 0.654
Indicates that the latter subgroup is directly compared with the former subgroup.
Indicates that the OR value could not be calculated because the number of PWE with metabolic cause was too small. ASM: Anti-seizure medication; CI: Confidence interval; COVID-19: Coronavirus disease 2019; OR: Odds ratio; PWE: Patients with epilepsy; –: Not available.

Sixty-seven PWE who had not been vaccinated and had recently withdrawn from or reduced ASMs were retrospectively included, and 11.9% (8/67) of them had seizure recurrence, while 25.9% (28/108) of those PWE who had been vaccinated and had recently withdrawn from or reduced ASMs had seizure recurrence. The results of binary logistic regression analysis showed that the vaccination against COVID-19 did not significantly affect the seizure recurrence rate of PWE who had the behavior of drug reduction or withdrawal (OR: 0.343, 95% CI: 0.082–1.437, P = 0.143). Details are shown in Supplementary Tables 2 and 3, https://links.lww.com/CM9/B401.

Results of the last EEG before vaccination

We obtained the results of the last EEG of 69 patients performed before vaccination. In the 69 PWE, 36 had normal EEG results, of which, three were in the SAV group. Whereas 33 had abnormal EEG results, of which, six were in the SAV group. The proportion of patients with normal EEG results having seizures after vaccination was lower than that of patients with abnormal EEG results (8.3% [3/36] vs. 18.2% [6/33]); however, the difference was not statistically significant (P = 0.294). Moreover, 32 of 33 patients (97.0%) who were seizure-free for more than 3 months before vaccination and whose EEG results were normal before vaccination did not develop any seizures within 14 days of vaccination.

Non-epileptic adverse reactions

A total of 92 (22.6%) patients experienced non-epileptic adverse reactions following vaccination. Among these patients, 58 (14.3%) experienced pain or itching at the injection site, 19 (4.7%) developed lumps or induration at the injection site, and eight (2.0%) experienced low-grade fever (37.1–38.0°C) after vaccination. Furthermore, 21 (5.2%) patients experienced fatigue, 15 (3.7%) experienced dizziness or headache, 22 (5.4%) had muscle soreness, four (1.0%) experienced nausea or vomiting, and three (0.7%) experienced stomachache or diarrhea. Patients with these adverse reactions could tolerate the condition and did not require any medical intervention. Only two (0.5%) patients experienced serious adverse reactions, including syncope and generalized rash. However, these adverse reactions were not significantly different between the SAV and SFAV groups (P > 0.05). Twelve of 92 PWE (13.0%) who experienced non-epileptic adverse events after vaccination experienced a post-vaccination seizure, compared with 36 of 315 PWE (11.4%) who did not experience non-epileptic adverse events; however, the difference was not statistically significant (P = 0.714), indicating that the non-epileptic adverse events after vaccination may not affect the seizures recurrence.


This study generated important data about the impact of COVID-19 vaccines on seizures among PWE. Results revealed that seizures (within 14 days after vaccination) occurred among some PWE (11.8%). Binary logistic regression analysis revealed that seizure-free duration and withdrawal of ASMs or reduction in dosage during the peri-vaccination period were correlative factors for the recurrence of seizures after vaccination. In addition, seizures after vaccination may be rare among PWE with normal EEG results. The present study assessed the risk for seizures among PWE after COVID-19 vaccination; as such, our findings may serve as a reference for vaccination in this patient population.

Currently, large-scale COVID-19 vaccination is ongoing in China, and many individuals, including PWE, are initially skeptical about the safety of vaccines. This study revealed that the safety of the COVID-19 vaccine merits recognition. Among the 407 patients included in this study, 92 (22.6%) experienced mild non-epileptic adverse reactions, whereas only two (0.5%) experienced serious adverse reactions. However, in this study, 11.8% of PWE experienced seizures within 14 days after vaccination, which is lower than the rate of seizures observed in patients with Dravet syndrome after vaccination. In patients with Dravet syndrome, the rates of seizures after pertussis and MMR vaccination have been reported to be 21% and 25%, respectively.[15] The difference may be because no patients were diagnosed with Dravet syndrome in this study. In another study, Top et al[16] found that the risk for seizures after vaccination with various vaccines did not increase. The recurrence of seizure after COVID-19 vaccination in our study may be explained by the following reasons. The majority of patients in the SAV group had a seizure-free duration of <3 months. Among these patients, in whom epilepsy control status was not ideal, the recurrence of seizures after vaccination may be attributed to the characteristics of epilepsy rather than the vaccination. Second, mental disorders (such as anxiety) can promote the onset of epilepsy.[17] Unlike DTP and MMR vaccinations, COVID-19 vaccination has only recently begun. Concerns regarding safety and efficacy of vaccine may exacerbate their condition or negate all previous efforts in anti-epileptic treatment over the years and incite inevitable worry among PWE, resulting in anxiety or other mental health problems and, consequently, promoting the occurrence or increasing the frequency of seizures.

Aladdin and Shirah[18] reported a case of refractory status epilepticus after ChAdOx1 nCoV-19 vaccination, which suggested that COVID-19 vaccination may lead to a seizure. Although DTP and MMR vaccines can promote seizures by inducing additional fever,[3,13] in this study, the eight patients who developed a fever after vaccination did not experience seizures. Coronaviruses, particularly Betacoronavirus, to which SARS-CoV-2 belongs, not only infect the respiratory tract but also invade the central nervous system (CNS).[19] SARS-CoV-2 can enter CNS through various ways as follows: it can spread through blood and cross the blood–brain barrier (BBB), it can spread across synapses, and it can enter through the blood-cerebrospinal fluid or structures around ventricles.[20] After entering CNS, the virus mainly binds with various nerve cells through angiotensin-converting enzyme 2.[20] Coronavirus mainly infects neurons in the brainstem associated with cardiopulmonary control; damage to these areas may aggravate respiratory depression and even lead to respiratory failure,[19] eventually increasing the risk of sudden epileptic death.[21] In addition, SARS-CoV-2 infection can induce a systemic inflammatory response and release many pro-inflammatory factors, thus destructing BBB, damaging glia limitans, and activating toll-like receptors in microglia and astrocytes, eventually promoting neuroinflammation, which may severely disrupt brain homeostasis and cause neuronal death.[22,23] Many studies have revealed that activation of toll-like receptors can cause epilepsy.[24,25] Moreover, BBB disruption can lead to the entry of immune cells and serum proteins from peripheral blood into the brain, promoting the occurrence of epilepsy.[25,26] Therefore, infection by SARS-CoV-2 may induce epilepsy directly through an inflammatory cascade. Currently available COVID-19 vaccines approved by the World Health Organization include ribonucleic acid (RNA) vaccines, viral vector vaccines, and inactivated vaccines. A meta-analysis revealed that among these three types of vaccines, the risk of total adverse reactions after vaccination with inactivated vaccines was the lowest (especially the risk of fever) as compared with the highest risk of total adverse reactions after RNA vaccination.[27] However, the inactivated vaccine had the lowest efficacy, whereas the RNA vaccine had the highest efficacy.[27] Therefore, the choice of a vaccine should be based on the local epidemic control of PWE.

In this study, binary logistic regression analysis revealed that the risk for seizure after vaccination was significantly higher among patients who experienced seizures within three months before vaccination than in seizure-free patients. In China, “uncontrolled epilepsy” is a contraindication to COVID-19 vaccination; however, no widely accepted, standard definition of “uncontrolled epilepsy” exists. One study defined uncontrolled epilepsy as experiencing a seizure within 12 months.[28] However, in this study, binary logistic regression analysis revealed that, among patients with a seizure-free duration >3 months, the seizure rate after vaccination did not change significantly, even if the duration was further extended. This means that vaccination is generally safe for PWE who have been seizure-free for >3 months. Horváth et al[29] found that the mortality rate of COVID-19 among PWE <50 years of age was 10 to 20 times higher than that reported in an epidemiological study. In addition, as mentioned earlier, the COVID-19 pandemic may worsen the condition of PWE.[8,9] Therefore, the protective effects of a COVID-19 vaccine are more important for PWE than for healthy individuals. Therefore, we suggest that PWE who experience seizures within 3 months before vaccination can also consider vaccination in cases of a high local prevalence of COVID-19. Another correlative factor with statistical significance was the withdrawal of ASMs or reduction in dosage during the peri-vaccination period. Therefore, we suggest that a reduction in the dosage of ASMs should be avoided during the peri-vaccination period. Whether patients with well-controlled seizures who have discontinued ASMs should resume their ASM regimen should be based on auxiliary examinations such as EEG and positron emission tomography/computed tomography. Moreover, patients who discontinue ASMs by themselves should resume their ASM regimen.

Furthermore, we included a factor that was not statistically significant but worthy of attention. Although the EEG results of 69 patients were not significantly different between the two groups, 32 of 33 patients (97.0%) who were seizure-free for 3 months before vaccination and had normal EEG results did not experience any seizures after vaccination. According to a meta-analysis by Lamberink et al,[30] abnormal EEG finding before drug withdrawal was a risk factor for seizure recurrence in PWE after drug withdrawal, which suggested that compared with PWE with abnormal EEG results, PWE with normal EEG results had a better seizure control status and were less likely to develop seizures induced by various factors.

This study had some limitations, the first of which included its retrospective design and small sample size. Second, seizure information was mainly obtained from the report by patients themselves or their relatives; therefore, seizures in some PWE may have been missed. Third, we divided seizure-free duration into five categories, the range of each category may be too wide which may affect the accuracy of the results. Fourth, because PWE were recruited primarily from outpatient clinics, potential selection bias may have led to PWE who were in stable condition before and after vaccination not being included, leading to an underestimation of the safety of the COVID-19 vaccine. Finally, because all the patients received inactivated vaccines, the results of this study may not be generalizable to other vaccine types. In the future, prospective randomized controlled studies with large sample sizes should be conducted to further evaluate the impact of COVID-19 vaccination on seizures among PWE.

In conclusion, this study revealed that 11.8% of PWE experienced recurrence of epilepsy after undergoing COVID-19 vaccination. However, this phenomenon was relatively rare among PWE who were seizure-free for >3 months and had normal EEG results before vaccination. Finally, PWE who discontinued ASMs or reduced their dosage during the peri-vaccination period were at a higher risk for seizures after vaccination, suggesting that ASM regimens should be adjusted accordingly in this patient population.


We would like to thank all the authors for their contributions to this research. In addition, we would also like to thank Lili Cao (Qilu Hospital of Shandong University), Zhaofu Chi (Qilu Hospital of Shandong University), Liling Yang (Provincial Hospital Affiliated to Shandong First Medical University), and Huaikuan Wu (The First Affiliated Hospital of Shandong First Medical University) for providing the data. Finally, we would like to thank Professor Shimin Hu (Xuanwu Hospital, Capital Medical University) for her contribution to the statistical work of the study.


This study was supported by a grant from the National Natural Science Foundation of China (No. 81873786).

Conflicts of interest



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