Overview

The Comirnaty vaccine is a messenger RNA (mRNA)-based vaccine indicated for active immunisation against COVID-19 infections caused by SARS-CoV-2.^1-2 It contains nucleotide-modified mRNA that encodes the viral spike (S) protein of SARS-CoV-2. When the vaccine is administered, the mRNA directs the temporary production of the S protein. The human body will recognise the protein as foreign (antigen), therefore eliciting antibody production and immune responses that may provide protection against COVID-19 infections during the contact with SARS-CoV-2.

In Malaysia, the Comirnaty vaccine is the only mRNA-based vaccine being used under the National COVID-19 Immunisation Programme (PICK).^3-4 There are currently five (5) Comirnaty vaccines registered with the Drug Control Authority (DCA).³ To date, 44.8 million doses of Comirnaty vaccines have been administered nationwide under PICK.⁵

Heavy menstrual bleeding is described as bleeding characterised by an increased menstrual volume and/or duration which interferes with the person’s physical, social wellbeing, emotional, and quality of life.^6-7

Background of the Safety Issue

In November 2022, the National Pharmaceutical Regulatory Agency (NPRA) learned from the European Medicines Agency (EMA) regarding the risk of heavy menstrual bleeding following the use of the Comirnaty vaccine.⁶

The EMA completed an assessment of this safety signal after evaluating data from relevant cases reported during clinical trials, observational studies, intensified post-marketing surveillance activities, and spontaneously reported cases.⁶ Based on the review of the available information, the EMA concluded that there is at least a reasonable possibility that the occurrence of heavy menstrual bleeding is causally associated with the Comirnaty vaccine. Therefore, the EMA recommended the updating of package insert for the Comirnaty vaccine to include heavy menstrual bleeding as a side effect of unknown frequency.

Heavy menstrual bleeding has been reported following first, second, and booster doses of the Comirnaty vaccine, of which a small number of cases reported a positive rechallenge upon the second dose.^6,8 However, most cases have been reported as non-serious and self-limiting.^6,9-11 There is currently no evidence linking the Comirnaty vaccine to negative effects on female reproduction, fertility, or pregnancy.

Menstrual disorders are common and in general can arise from a range of extrinsic or intrinsic factors such as stress, endocrine, gynaecological, autoimmune, nutrition, genetics, infection, and changes in lifestyle.^9-10 Recent studies also suggest that the observed menstrual cycle irregularities during the pandemic period may be influenced by the SARS-CoV-2 infection itself, pandemic-related stress, and COVID-19 vaccines.

While the exact mechanism underlying how the Comirnaty vaccine causes menstrual irregularities is still obscure, potential explanations have been proposed.^7,9-10 The vaccine renders activation of immune cells via the production of pro-inflammatory markers to prevent or alleviate future COVID-19 infections.^9-10 Consequently, the vaccine-induced activation of endometrial innate immune cells that regulate cyclic breakdown, regeneration and repair of the endometrium could lead to heavier and irregular menstrual bleeding. Other plausible hypotheses include vaccine-induced immunological changes, such as thyroid abnormalities that affects levels of hormones regulating menstruation, as well as thrombocytopenia that has also been observed with many vaccines. Additionally, vaccine-associated stress might temporarily affect the hypothalamic-pituitary-ovarian axis.^9-11

Adverse Drug Reaction Reports¹²

To date, the NPRA has received a total of 19,904 reports with 44,234 adverse events suspected to be related to the Comirnaty vaccine.* Of these, 16 reports involved heavy menstrual bleeding following the administration of the Comirnaty vaccine. Other reported events pertaining to post-vaccination menstrual changes include menstruation irregular (11), dysmenorrhoea (3), amenorrhoea (1), intermenstrual bleeding (1), menstruation delayed (1), and menstrual cycle prolonged (1).

*Note: No reports of adverse events related to the use of the Comirnaty bivalent vaccine have been received by the NPRA, as it has only recently been registered in December 2022 and has not yet been used in Malaysia.

Advice for Health Care Professionals

• Be aware of the potential risk of heavy menstrual bleeding following the administration of the Comirnaty vaccine.
• Reassure vaccine recipients that current clinical evidence indicates that post-vaccination menstrual changes are mostly non-serious, transient, and of no long-term clinical consequences on female reproduction, fertility, or pregnancy.
• Advise vaccine recipients to seek medical attention if they experience any unusual menstrual changes, including postmenopausal bleeding, that worsen, persist over several cycles, or impact their daily activities.
• Report all adverse events suspected to be related to the use of the Comirnaty vaccine or other COVID-19 vaccines to the NPRA.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). COMIRNATY concentrate for dispersion for infection [Package Insert]. QUEST3+ Product Search. 2023 Jan [cited 2023 Jan 17]. Available from: http://www.npra.gov.my
2. European Medicines Agency (EMA). Comirnaty [Internet]. 2022 Nov 10 [cited 2023 Jan 17]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST 3+ system [Internet]. 2023 [cited 2023 Jan 18]. Available from: https://www.npra.gov.my
4. National Pharmaceutical Regulatory Agency (NPRA). Summary Report on Adverse Events Following Immunisation of COVID-19 Vaccines in Malaysia (Data as of 31st Dec 2022) [Internet]. 2023 [cited 2023 Mar 12]. Available from: https://www.npra.gov.my/easyarticles/images/users/1066/AEFI%20Summary/COVID-19-Vaccines_AEFI-Summary-Report_V6-data-as-of-20221231.pdf
5. Ministry of Health, Malaysia. COVID19-public [Internet]. Github. 2023 [cited 2023 Jan 12]. Available from: https://github.com/MoH-Malaysia/covid19-public 
6. European Medicines Agency (EMA). Covid-19 vaccines safety update [Internet]. 2022 Nov10 [cited 2023 Jan 17]. Available from: https://www.ema.europa.eu/en/documents/covid-19-vaccine-safety-update/covid-19-vaccines-safety-update-10-november-2022_en.pdf
7. Davies J, Kadir RA. Heavy menstrual bleeding: an update on management. Thrombosis Research. 2017; Mar 1;151:S70-7. Available from: https://doi.org/10.1016/S0049-3848(17)30072-5
8. The Netherlands Pharmacovigilance Centre Lareb. Heavy menstrual bleeding in product information Pfizer and Moderna vaccines [Internet]. 2022 Nov 10 [cited 2023 Jan 17]. Available from: https://www.lareb.nl/en/news/heavy-menstrual-bleeding-in-product-information-pfizer-and-moderna-vaccines?year=2022&query=#:~:text=The%20EMA%20recommended%20to%20add,heavy%20menstrual%20bleeding%20until%20now
9. Taşkaldıran I, Vuraloğlu E, Bozkuş Y, Turhan İyidir Ö, Nar A, Başçıl Tütüncü N. Menstrual Changes after COVID-19 Infection and COVID-19 Vaccination. International Journal of Clinical Practice. 2022; vol. 2022, Article ID 3199758, 5 pages. Available from: https://doi.org/10.1155/2022/3199758Oct 27;2022
10. Nazir M, Asghar S, Rathore MA, Shahzad A, Shahid A, Khan AA, Malik A, Fakhar T, Kausar H, Malik J. Menstrual abnormalities after COVID-19 vaccines: a systematic review. Vacunas. 2022;23(S2):S77-S87. Available from: https://doi.org/10.1016/j.vacun.2022.07.001
11. Lessans N, Rottenstreich A, Stern S, Gilan A, Saar TD, Porat S, Dior UP. The effect of BNT 162b2 SARS‐CoV‐2 mRNA vaccine on menstrual cycle symptoms in healthy women. International Journal of Gynecology & Obstetrics. 2022;160(1):313-8. Available from: https://doi.org/10.1002/ijgo.14356
12. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2023 [cited 2023 Jan 12]. Available from: https://www.npra.gov.my (access restricted)

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Wo Wee Kee
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali