Association of Facial Paralysis With mRNA COVID-19 Vaccines: A Disproportionality Analysis Using the World Health Organization Pharmacovigilance Database | Facial Nerve | JAMA Internal Medicine | JAMA Network
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Figure.  Forest Plot of the Information Component Values of mRNA COVID-19 Vaccine–Related Facial Paralysis vs All Other Viral Vaccines and Influenza Vaccines Alone
Forest Plot of the Information Component Values of mRNA COVID-19 Vaccine–Related Facial Paralysis vs All Other Viral Vaccines and Influenza Vaccines Alone

Number of facial paralysis cases (No. of cases) and total number of adverse drug reaction cases (Total No.) reported in the World Health Organization pharmacovigilance database are described. Broad definitions of facial paralysis correspond to the following Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs): facial nerve disorder, facial paralysis, facial paresis, facial spasm, oculofacial paralysis, VIIth nerve injury; narrow definition, only to the facial paralysis PT. CrI indicates credible interval.

Table.  Characteristics of mRNA COVID-19 Vaccine–Related Facial Paralysis Cases Reported in the WHO Pharmacovigilance Database
Characteristics of mRNA COVID-19 Vaccine–Related Facial Paralysis Cases Reported in the WHO Pharmacovigilance Database
1.
Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577 PubMedGoogle ScholarCrossref
2.
Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389 PubMedGoogle ScholarCrossref
3.
Bate  A, Lindquist  M, Edwards  IR,  et al.  A Bayesian neural network method for adverse drug reaction signal generation.   Eur J Clin Pharmacol. 1998;54(4):315-321. doi:10.1007/s002280050466 PubMedGoogle ScholarCrossref
4.
Holland  NJ, Bernstein  JM.  Bell’s palsy.   BMJ Clin Evid. 2014;2014:1204.PubMedGoogle Scholar
5.
Kamath  A, Maity  N, Nayak  MA.  Facial paralysis following influenza vaccination: a disproportionality analysis using the Vaccine Adverse Event Reporting System Database.   Clin Drug Investig. 2020;40(9):883-889. doi:10.1007/s40261-020-00952-0PubMedGoogle ScholarCrossref
6.
Rowhani-Rahbar  A, Klein  NP, Lewis  N,  et al.  Immunization and Bell’s palsy in children: a case-centered analysis.   Am J Epidemiol. 2012;175(9):878-885. doi:10.1093/aje/kws011 PubMedGoogle ScholarCrossref
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    3 Comments for this article
    EXPAND ALL
    Facial palsy
    Ted Zollman, MD | Speciality
    I understand this adverse event is rare and appears to be no more common with these vaccines than with others, but I saw a patient in my clinic with a facial palsy that developed within a few days of the COVID-19 vaccine. The benefits outweigh the risks, but the risks are not zero. I’m certain the patient will do well, and the palsy will hopefully resolve, but the eye will have to be monitored closely over the near term.
    CONFLICT OF INTEREST: None Reported
    Lack of Association
    Cloyd Gatrell, MD |
    Lack of Association of Facial Paralysis with mRNA COVID-19 Vaccines would be a more accurate title, and less likely to heighten vaccine hesitancy.
    CONFLICT OF INTEREST: None Reported
    Gold Standard for determining the risk of facial paralysis(FP)from vaccines:comparing the incidence of FP against an unvaccinated population
    Pablo Tapia | Hospital La Florida, Santiago, From Chile
    Research like this as the vaccinated population increases is essential in evaluating the safety of SARS-Cov-2 vaccines in the real world. I congratulate the authors.

    The emphasis of the study is placed on the frequency of facial paralysis in relation to other vaccines. In a smaller scale vaccination, a 0.6% incidence of facial paralysis could be an acceptable risk versus benefits. However, with billions of people vaccinated, we could have a “small epidemic” of facial paralysis attributable (if causality exists) to mRNA COVID-19 vaccines.

    Another fundamental point that is not considered in the current study is: what is
    the incidence of facial paralysis in an unvaccinated population with similar characteristics? Since depending on how safe (or not) the vaccine used for the comparison is the risk assessment of the mRNA COVID-19 Vaccines.

    In the second comment, Cloyd Gatrell, MD, (April 29, 2021) proposes an alternative title of lack of association "Lack of Association of Facial Paralysis with mRNA COVID-19 Vaccines", which is however imprecise. Although it is essential to encourage the population to be vaccinated, the current study does not provide data to conclude that there is a lack of association between current vaccination and the occurrence of facial paralysis, but only that the risk is like that found with other antiviral vaccines.
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    April 27, 2021

    Association of Facial Paralysis With mRNA COVID-19 Vaccines: A Disproportionality Analysis Using the World Health Organization Pharmacovigilance Database

    Author Affiliations
    • 1Pharmacovigilance Department, Grenoble Alpes University Hospital, Grenoble, France
    • 2Clinical Pharmacology Department, Inserm CIC1406, Grenoble Alpes University Hospital, Grenoble, France
    • 3Inserm UMR U1300-HP2 Laboratory, University Grenoble Alpes, Grenoble, France
    JAMA Intern Med. Published online April 27, 2021. doi:10.1001/jamainternmed.2021.2219

    During the pivotal phase 3 clinical trials of mRNA COVID-19 vaccines, several cases of facial paralysis were observed in the vaccine groups (7 of 35 654) compared with 1 case among people who received placebo (1 of 35 611).1,2 Although a causal relationship could not be established from clinical trials, the US Food and Drug Administration recommended monitoring vaccine recipients for facial paralysis. We thus explored this potential safety signal through a disproportionality analysis using the World Health Organization pharmacovigilance database, VigiBase.

    Methods

    Disproportionality analyses are hypothesis-generating methods that aim to detect putative associations between drugs and adverse drug reactions. Such methods quantify the extent to which a drug–event combination occurs disproportionally compared with what would be expected in the absence of any association, but they do not provide risk quantification because the population actually exposed to the drugs is unknown. Several frequentist, multivariate, and Bayesian disproportionality methods have been developed to date. In this study, we generated disproportionality signals through the Bayesian neural network method, which was deemed significant if the lower boundary of the 95% credible interval of the information component (IC025) was greater than 0.3 The CECIC Rhône-Alpes-Auvergne, Clermont-Ferrand, IRB 5891 determined that institutional review board approval and informed consent were not necessary owing to the use of retrospective, deidentified data.

    Briefly, we performed 4 analyses with 2 control groups (all other viral vaccines and restricted to influenza vaccines) and 2 facial paralysis definitions (broad and narrow). All analyses were adjusted for sex and age. The statistical analysis was performed with R, version 3.6.2 (R Foundation). Details on methods used are presented in the eMethods in the Supplement.

    Results

    On March 9, 2021, among the 133 883 cases of adverse drug reactions reported with mRNA COVID-19 vaccines in the World Health Organization pharmacovigilance database, we identified a total of 844 (0.6%) facial paralysis-related events, including 683 cases of facial paralysis, 168 cases of facial paresis, 25 cases of facial spasms, and 13 cases of facial nerve disorders (some adverse events were coreported in the same case). A total of 749 cases were reported with the Pfizer-BioNTech vaccine, and 95 cases were reported with the Moderna vaccine. Of the 844 patients, 572 were female (67.8%), and the median (interquartile range) age was 49 (39-63) years. The median (range) time to onset was 2 (0-79) days. Case characteristics are summarized in the Table. Moreover, we identified 5734 (0.5%) and 2087 (0.7%) cases of facial paralysis among the 1 265 182 cases of adverse drug reactions reported with other viral vaccines and the 314 980 cases reported with influenza vaccines, respectively. We did not detect any signal of disproportionality of facial paralysis for broad and narrow definitions vs other viral vaccines (IC025 = −0.01 and IC025 = −0.06) or influenza vaccines alone (IC025 = −1.36 and IC025 = −0.32) (Figure).

    Discussion

    Facial paralysis can be observed in the context of many conditions, such as viral infections, traumatic injury, cancers, or hormonal changes during pregnancy. Idiopathic causes, also known as Bell palsy, are unilateral, generally reverse spontaneously, and cause partial or complete acute weaknesses of the face.4 Isolated facial paralysis after vaccination has been reported as case reports for decades with almost all viral vaccines, and it is thought to be immune mediated or induced by viral reactivations (eg, reactivation of a herpes virus infection).5 However, to date, pharmacoepidemiological studies have failed to identify a higher risk of facial paralysis after vaccination.5,6

    When compared with other viral vaccines, mRNA COVID-19 vaccines did not display a signal of facial paralysis. As of March 9, 2021, more than 320 million COVID-19 vaccine doses had been administered worldwide. Therefore, despite selective reporting and a potential delay in reporting and transferring cases among pharmacovigilance databases, the reporting rate of facial paralysis after mRNA COVID-19 vaccination found in the present study is not higher than that observed with other viral vaccines. Although we adjusted for sex and age, residual confounding and reporting bias may influence the results. To conclude, if an association between facial paralysis and mRNA COVID-19 vaccines exists, the risk is likely very low, as with other viral vaccines.

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    Article Information

    Accepted for Publication: March 31, 2021.

    Published Online: April 27, 2021. doi:10.1001/jamainternmed.2021.2219

    Corresponding Author: Charles Khouri, PharmD, Pharmacovigilance Department, University Grenoble Alpes and Grenoble Alpes University Hospital, Centre Regional de Pharmacovigilance, CHU Grenoble Alpes, CS 10217, 38043 Grenoble Cedex 9, France (ckhouri@chu-grenoble.fr).

    Author Contributions: Dr Khouri had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Mr Renoud and Dr Khouri served as co–first authors.

    Concept and design: Khouri, Revol, Perez, Cracowski.

    Acquisition, analysis, or interpretation of data: Renoud, Khouri, Lepelley, Roustit, Cracowski.

    Drafting of the manuscript: Renoud, Khouri.

    Critical revision of the manuscript for important intellectual content: Khouri, Revol, Lepelley, Perez, Roustit, Cracowski.

    Statistical analysis: Renoud, Khouri, Revol, Perez.

    Administrative, technical, or material support: Renoud.

    Supervision: Khouri, Lepelley, Cracowski.

    Conflict of Interest Disclosures: None reported.

    Disclaimer: The information does not represent the opinions of the Uppsala Monitoring Centre or the World Health Organization.

    Additional Information: We thank VigiBase for giving us access to the data. The data supplied to VigiBase come from a variety of sources, and the likelihood of a causal relationship is not the same in all reports.

    References
    1.
    Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577 PubMedGoogle ScholarCrossref
    2.
    Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389 PubMedGoogle ScholarCrossref
    3.
    Bate  A, Lindquist  M, Edwards  IR,  et al.  A Bayesian neural network method for adverse drug reaction signal generation.   Eur J Clin Pharmacol. 1998;54(4):315-321. doi:10.1007/s002280050466 PubMedGoogle ScholarCrossref
    4.
    Holland  NJ, Bernstein  JM.  Bell’s palsy.   BMJ Clin Evid. 2014;2014:1204.PubMedGoogle Scholar
    5.
    Kamath  A, Maity  N, Nayak  MA.  Facial paralysis following influenza vaccination: a disproportionality analysis using the Vaccine Adverse Event Reporting System Database.   Clin Drug Investig. 2020;40(9):883-889. doi:10.1007/s40261-020-00952-0PubMedGoogle ScholarCrossref
    6.
    Rowhani-Rahbar  A, Klein  NP, Lewis  N,  et al.  Immunization and Bell’s palsy in children: a case-centered analysis.   Am J Epidemiol. 2012;175(9):878-885. doi:10.1093/aje/kws011 PubMedGoogle ScholarCrossref
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