BACKGROUND: Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to reduce the risk of developing Coronavirus Disease 2019 (COVID-19). Despite the significant benefits in terms of reduced risk of hospitalization and death, different adverse events may present after vaccination: among them, headache is one of the most common, but nowadays there is no summary presentation of its incidence and no description of its main features. METHODS: We searched PubMed and EMBASE covering the period between January 1st 2020 and August 6th, 2021, looking for record in English and with an abstract and using three main search terms (with specific variations): COVID-19/SARS-CoV-2; Vaccination; headache/adverse events. We selected manuscript including information on subjects developing headache after injection, and such information had to be derived from a structured form (i.e. no free reporting). Pooled estimates and 95% confidence intervals were calculated. Analyses were carried out by vaccine vs. placebo, by first vs. second dose, and by mRNA-based vs. "traditional" vaccines; finally, we addressed the impact of age and gender on post-vaccine headache onset. RESULTS: Out of 9338 records, 84 papers were included in the review, accounting for 1.57 million participants, 94% of whom received BNT162b2 or ChAdOx1. Headache was generally the third most common AE: it was detected in 22% (95% CI 18-27%) of subjects after the first dose of vaccine and in 29% (95% CI 23-35%) after the second, with an extreme heterogeneity. Those receiving placebo reported headache in 10-12% of cases. No differences were detected across different vaccines or by mRNA-based vs. "traditional" ones. None of the studies reported information on headache features. A lower prevalence of headache after the first injection of BNT162b2 among older participants was shown. CONCLUSIONS: Our results show that vaccines are associated to a two-fold risk of developing headache within 7 days from injection, and the lack of difference between vaccine types enable to hypothesize that headache is secondary to systemic immunological reaction than to a vaccine-type specific reaction. Some descriptions report onset within the first 24 h and that in around one-third of the cases, headache has migraine-like features with pulsating quality, phono and photophobia; in 40-60% of the cases aggravation with activity is observed. The majority of patients used some medication to treat headache, the one perceived as the most effective being acetylsalicylic acid.

1st Neurology Department Medical School Eginition University Hospital National and Kapodistrian University of Athens Athens Greece

Ambulatorio Per La Diagnosi E Cura Delle Cefalee Centro Medico Visconti Di Modrone Milan Italy

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Hospital of Rome Rome Italy

CNAP Center for Sensory Motor Interaction Department of Health Science and Technology Faculty of Medicine Aalborg University Aalborg Denmark

Deparment of Internal Medicine Sapienza University Rome Italy

Departement of Neurology Headache Center Charité Universitaetsmedizin Berlin Berlin Germany

Department of Anatomy and Neuroscience Faculty of Medicine University J J Strossmayer Osijek Croatia

Department of Clinical and Molecular Medicine Sapienza University Rome Italy

Department of Health Promotion Mother and Child Care Internal Medicine and Medical Specialties Policlinico Universitario P Giaccone University of Palermo Palermo Italy

Department of Neurology 3rd Faculty of Medicine Charles University and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Neurology Kingston Hospital London UK

Department of Neurology Regional Hospital of Shkodra Shkoder Albania

Department of Neurology School of Medicine Istanbul Medipol University Istanbul Turkey

Department of Neurology St George's University Hospital London UK

Department of Neurology University Emergency Hospital of Bucharest Bucharest Romania

Department of Neurology University Hospital Center Osijek Osijek Croatia

Department of Neurology University Medicine Greifswald Greifswald Germany

Department of Neurology Wroclaw Medical University Wroclaw Poland

Department of Neurosciences Rita Levi Montalcini University of Torino Turin Italy

Department of Neurosciences Università Cattolica del Sacro Cuore Rome Italy

Department of Psychiatry Division of Consultation Psychiatry and Neuroscienc Wroclaw Medical University Wroclaw Poland

Division of Vascular Medicine and Pharmacology Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands

General Practice Moscow Russia

General Practice Orzyny Poland

Headache Center Department of Advanced Medical and Surgical Sciences University of Campania Luigi Vanvitelli Naples Italy

Headache Center Educational and Scientific Medical Complex University Clinic of Karkiv National Medical University Karkiv Ukraine

Headache Clinic Terapia Neurologiczna 'Samodzielni' Warsaw Poland

MIGRE Polish Headache Center Wroclaw Poland

Neurofisiopatologia Dipartimento Di Scienze Dell'invecchiamento Neurologiche Ortopediche E Della Testa Collo Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Neurology and Clinical Genetics Department Kyrgyz State Medical Academy Bishkek Kyrgyzstan

Neurology and Neurophysiology Service Pain Medicine Unit Santa Maria Maddalena Hospital Occhiobello Italy

Neurology Clinic Department of Neurology Tartu University Hospital Tartu Estonia

Neurology Department Republican Diagnostic Centre Makhachkala Russia

Neuroscience Section Department of Applied Clinical Sciences and Biotechnology University of L'Aquila L'Aquila Italy

Outpatient Service Pogradec Hospital Pogradec Albania

Rd Neurology Department of Cerebrovascular Diseases and Cognitive Impairments Research Center of Neurology Moscow Russia

Regional Referral Headache Center Sant'Andrea University Hospital Rome Italy

Thriassio General Hospital of Elefsina Elefsina Greece

UOC Neurologia Salute Pubblica Disabilità Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

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