As of 13 December, 2022, 34,374 EEA cases of the PT ‘heavy menstrual bleeding’ following the administration of any COVID-19 vaccine had been reported to EV. After excluding cases with missing or incomplete information on vaccine administration date or reaction date and selecting cases where sex was specified as female, 23,884 cases remained. Ninety-one percent of the cases were reported following administration of an mRNA-based COVID-19 vaccine: 76% with Comirnaty Original and 15% with Spikevax Original. Table 2 describes the demographics of the EEA cases for both vaccines. The first case of heavy menstrual bleeding in the study period was reported to EV on 6 January, 2021.

In terms of primary source country, over a third of the total cases for Comirnaty Original were reported in the Netherlands, while one third of the cases for Spikevax Original were reported in Germany (Table 2). In fact, for Comirnaty Original, the Netherlands was the primary country (28–39%) in terms of the number of reports of the PT ‘heavy menstrual bleeding’ for all the cases concerning consumers aged under 55 years (Table 2). Furthermore, cases originating from the Netherlands accounted for 29% of the total cases for Comirnaty Original, while the proportion of cases originating from the Netherlands accounted for 8.7% of all the other medicinal products and adverse events (581,044 of 6,703,290 EEA cases of 13 December, 2022). Details on EV cases reported by vaccine (original versions) and country can be found in Table 1 of the ESM.

We analysed the trend of the LCI of the ROR for heavy menstrual bleeding and COVID-19 vaccines from January 2021 to December 2022 to identify the point in time when the ROR LCI reached the LCI threshold. The analysis was stratified by vaccine type (mRNA-based compared to other COVID-19 vaccines). We found that for mRNA-based COVID-19 vaccines, the LCI of the ROR reached the LCI threshold for an SDR in August 2021, and increased exponentially until March 2022 (Fig. 1A). Over the same period, the increase in the LCI was notably higher when restricting the case reports to those notified directly by consumers. In contrast, for COVID-19 vaccines not based on mRNA platforms, the LCI of the ROR using only spontaneous reports notified directly by consumers did not reach the LCI threshold during the study period (Fig. 1B). For COVID-19 vaccines not based on mRNA platforms, spontaneous reports notified by healthcare professionals reached the LCI threshold for an SDR in June 2021. However, the magnitude of the disproportionality was small compared with mRNA-based COVID-19 vaccines, and the ROR decreased from August 2021.

Reporting odds ratio for messenger RNA (mRNA)-based COVID-19 vaccines (European Economic Area [EEA] cases). Dynamic reporting odds ratio for EEA cases for mRNA based (A) and other (B) COVID-19 vaccines and heavy menstrual bleeding. All the COVID-19 vaccines were used for a pooled reporting odds ratio calculation. The suspected adverse drug reaction was defined using the MedDRA Preferred Term “Heavy menstrual bleeding”. The mRNA-based COVID-19 vaccines included Comirnaty Original, Spikevax Original (previously COVID-19 Vaccine Moderna), Comirnaty Original/Omicron BA.1, Spikevax Original/Omicron BA.1, Comirnaty Original/Omicron BA.4-5 and Spikevax Original/Omicron BA.4-5. Other COVID-19 vaccines included Vaxzevria (previously COVID-19 Vaccine AstraZeneca), Jcovden (previously COVID-19 Vaccine Janssen) and Nuvaxovid. LCI lower confidence interval

To investigate changes in the reporting of heavy menstrual bleeding, the date when the adverse drug reaction occurred (reaction start date) and the date when the report was first received from the primary source (receive date) were extracted for all the cases and used to visualise the distribution of cases over time. The number of cases per COVID-19 vaccine occurring weekly, based on the reaction start date is shown in Fig. 2A, while the number of cases received per week, based on the receive date is shown in Fig. 2B. A more even distribution is observed when the cases are distributed based on the reaction start date (Fig. 2A) compared to the distribution based on the receive date (Fig. 2B), which could be explained by a delayed reporting of the reaction by the primary source and/or the delay in the processing of reports (weeks 20–35 covering from 1 June to 31 August, 2021; and week 51 covering from 20 December to 26 December, 2021).

Weekly cases reported to EudraVigilance by vaccine brand and reaction start date (A) and receive date (B) during the study period i.e. from 1 January, 2021 to 13 December, 2022

Figure 2A shows two peaks in 2021, one that reaches the maximum of 1000 cases on week 31 of 2021 (week starting 2 August) and another that reaches 250 cases in week 51 of 2021 (starting 20 December). Figure 2B shows the same peak in week 31 of 2021 with the highest number of cases (approximately 1500), a second peak in week 39 of 2021 (starting 27 September) of just above 500 cases which is not observed in Fig. 2A, a third peak in week 51 of 2021 with approximately 800 cases and a fourth peak of just above 500 cases in week 29 of 2022. Discrepancies between these figures could be explained by reports submitted days or months after the reaction.

To investigate to what extent media attention could influence the reporting of heavy menstrual bleeding submitted over the course of the vaccination campaign, the median reporting time was calculated as detailed in Methods. From week 24 (starting 14 June) to week 35 (starting 30 August) of 2021, the median reporting time ranged from 10 to 25 days for Comirnaty Original (Fig. 3). From week 36 (starting 6 September), the median reporting time increased and ranged from 30 days to over 3 months. At the beginning of 2022, the median reporting time dropped again to approximately 30 days following an increase in the case reports; however, it soon increased linearly. Similar trends of smaller magnitude were observed for Spikevax Original (Fig. S2 of the ESM). Of note, for this vaccine, the last EEA case of heavy menstrual bleeding was reported to EV in February 2022.

Median reporting time (days) and number of cases received per week for Comirnaty Original. The median reporting time was calculated by week (blue line) using the median value of the difference in days between the receive date and reaction start date per case. The weekly number of cases based on the receive date is indicated by the right axis and shown by the grey area

An alternative approach to investigate the changes in reporting over time would be to explore the median reporting time in relation to the number of weekly cases by reaction start date (Figs. S3–S4 of the ESM). Cases occurring in the early phases of the vaccination campaign had an increased reporting time, while over longer time, the trend is decreasing.

When stratifying the cases by country, the peaks in reporting corresponding to weeks 31, 39 and 51 of 2021, respectively, were explained by cases originating from the Netherlands, and the peak of week 29 of 2022 because of cases received in France (Fig. 4).

Weekly European Economic Area (EEA) cases received of heavy menstrual bleeding following administration of a Comirnaty Original for the four countries that accounted for 77% of the case reporting

We identified a total of 3944 articles for 27 out of the 30 EEA countries. The three countries for which media outlets were not identified were Cyprus, Luxembourg and Lichtenstein; media outlets in these countries may have been covered by the Greek, German or French media outlets, respectively.

Over 100 articles were published across the EEA during 6 weeks (Fig. 5). The coverage was further stratified by country to investigate how each country contributed to the total EEA coverage, and to facilitate the identification of events triggering the spikes in media coverage (Fig. 6).

Media coverage of the European Economic Area by week for articles mentioning COVID-19 and menstrual disorders. The dashed line indicates an arbitrary threshold of 100 articles

Media coverage by country and week for articles mentioning COVID-19 vaccines and menstrual disorders. The dashed vertical lines indicate key dates when over 100 articles were published across the European Economic Area. The scale of the y-axis is not fixed to facilitate visualising trends within countries

During week 31 of 2021 (starting 2 August), 114 articles were published across 14 EEA countries, of which 85 (75%) were published in France and the Netherlands. On 30 July, 2021, the French Medicines Agency (ANSM) included menstrual disorders in its latest pharmacovigilance update [19]. The Netherlands Pharmacovigilance Centre (Lareb) also published in their biweekly safety updates that over a thousand menstrual disorder reports had been received following COVID-19 vaccination [20].

The second peak observed during the study period corresponded to week 38 of 2021 (starting 20 September), when 119 articles were published in ten different countries. However, up to 74% of the articles were published in Germany and mentioned a safety update issued on 19 August, 2021 by the Paul-Ehrlich-Institut, the authority responsible for monitoring the safety of vaccines and biomedicines in Germany, on COVID-19 vaccines and suspected adverse events following vaccination, including irregularities of the menstrual cycle [21].

During week 51 of 2021 (starting 20 December), 154 articles were published in 12 different EEA countries, of which 103 (70%) were originated in Norway and the Netherlands. The Norwegian Institute of Public Health published an article on the increased incidence of menstrual changes among young women after coronavirus vaccination [22] on 21 December, 2021, while Lareb published a report on menstrual disorders and postmenopausal bleeding after administration of COVID-19 vaccines 1 day later [23].

The spike observed throughout week 4 of 2022 (starting 24 January) was preceded by articles published in Germany (154 out of 202 articles in the EEA), which were related to a prospective population-based study from the USA with evidence indicating that COVID-19 vaccination was associated with a change of less than 1 day in menstrual cycle length but no change in menses length [24]. On 27 October, 2022 (week 43), PRAC recommended that “heavy menstrual bleeding” should be included as a listed side effect for both Comirnaty and Spikevax, which was reflected in the EMA highlights from the respective PRAC meeting [16]. Within 2 weeks of the press release, over 216 articles were published in 20 countries.

To investigate the relationship between media events identified in the previous section and trends in case reporting, the number of publications were compared to the counts of cases per week in the respective countries (Fig. 7). This analysis showed that in general, media outlet publications were either coincidental or preceded the EV spikes in reporting. For example, there is a temporal correlation between increases in media events and case reporting in the Netherlands and the Lareb safety updates discussing menstruation changes (Fig. 8) after vaccination with COVID-19 vaccines. Similarly, a spike in reporting was observed in France in week 29 of 2022, shortly after a safety communication from the French National Agency for Drug Safety (ANSM) in which the regulators encouraged those who have observed changes in their menstrual cycle to report them [25]. Other countries also showed an overlap of media events and case reporting; however, the reporting to EV was of lower magnitude (Fig. 8).

Overlapping of the cases per week by received date (red) and the number of media outlets (grey). The dashed vertical lines indicate the key publications mentioned in Results. Countries with fewer than 20 cases reported to EudraVigilance are not included in the figure

Number of cases by reaction date (top) and received date (bottom) for Comirnaty in days for the Netherlands. The dashed vertical lines indicate the key publications mentioned in Results

Nonetheless, reports of heavy menstrual bleeding for Comirnaty Original were received since the beginning of the mass vaccination campaign as shown in Fig. 7. Notably, increased reporting was not observed following the publication of the PRAC recommendation to add heavy menstrual bleeding to the product information as a side effect of unknown frequency of the mRNA-based COVID-19 vaccines Comirnaty and Spikevax.