3.1 Registered Individuals

Over 1.4 million invitations were sent out during the study period. A total of 36,604 individuals (2.5%) registered with the YCVM, with the first individual registering in November 2020 and the last registration within the study period in December 2022. The number of registrations and submissions by calendar month and year are shown in Fig. 1. The time period for the majority of registrations aligns with the period in which first doses were initially offered in the UK, while peaks in later submissions align with the offer of second and subsequent doses. A total of 190,034 submissions were submitted by the 36,604 registered individuals during the study period. The median number of submissions submitted was 3 (interquartile range (IQR): 2–7).

Fig. 1

Number of registrations and submissions to the Yellow Card Vaccine Monitor up to 31 December 2022

Table 1 presents the demographics of individuals registered in the YCVM and the subset of those who reported a vaccination during their follow-up time in the YCVM. The median age of the cohort reported at registration was 62 years (IQR: 42–73). 10,791 (35.6%) of those reporting a vaccination had a registration date before their first vaccination, while 14,369 (47.5%) registered after the date of their first vaccination. Despite vaccination only being recommended in individuals aged 5+ years in the UK within the study period, 63 individuals reported an age < 5 years. The median age amongst those who had reported a vaccination was 63 years (IQR: 43–74). Other demographics of those reporting a vaccination were also broadly the same as those registering. The median follow-up in those reporting a vaccination was 184 patient days (IQR: 14–367, range 1–697), and 82.1% of the total follow-up time was from those aged 50 years or older. Female individuals contributed slightly more to YCVM than males, approximately 55% of the total follow-up time. Females were predominant contributors amongst the younger age groups up until the 70- to 79-year age group, with particularly greater levels of follow-up in the 50- to 59-year and 30- to 39-year age groups compared to men (median 273 vs. 264 patient days and 60 vs. 52 patient days, respectively). In the older age groups, men contributed greater levels of follow-up than females (median 181 days vs. 93 patient days amongst the ≥ 80-year age group, and 324 vs. 286 patient days in the 70- to 79-year age group). The follow-up time stratified by the sex of the individuals is presented in OSM Resource 2 to support contextualisation of the analyses on vaccinations in pregnancy.

Table 1 Number of individuals registered in the Yellow Card Vaccine Monitor (YCVM) stratified by vaccination reporting status and the total follow-up time accumulated in vaccinated individuals3.2 COVID-19 Vaccinations Reported

The demographics of individuals stratified by the vaccination brand(s) they reported receiving across all doses (N = 56,371) are presented in Table 2. An individual could receive doses from different product brands during their COVID-19 vaccination regimen, therefore an individual could appear in more than one column. Data are presented for the Pfizer, AstraZeneca, and Moderna monovalent vaccines. Of those reporting receiving another vaccine brand, two individuals reported receiving a Moderna bivalent vaccine, ten a Novavax vaccine, and two a Janssen vaccine.

Table 2 Demographics of individuals stratified by vaccine brand administered (percentage of doses reported for the vaccine brand, %)

Table 3 presents a summary of the number and demographics of individuals reporting a vaccination stratified by dose number and vaccine brand. In addition, three individuals reported a sixth dose. The median age of individuals in the subgroup reporting for fourth or fifth doses was older compared to those reporting primary vaccination doses. This reflects the narrowing eligibility criteria for booster doses. The higher median age of individuals reporting a first or second dose of the AstraZeneca vaccine reflects the advised preferential use of alternatives in individuals aged < 40 years following the signal of thrombosis with thrombocytopenia adverse reactions. Amongst those who reported receiving a first dose, 11.5% (n = 3146) were identified as immunocompromised. The proportion of immunocompromised individuals increased across the doses, with 11.5% (n = 1691) in second-dose, 12.2% (n = 1217) in third-dose, 15.5% (n = 527) in fourth-dose, and 25.1% (n = 242) in fifth-dose recipients. Again, this reflects the narrowing eligibility criteria for booster doses. The proportion of reported vaccines marked as unknown or ‘other’ brand increased slightly with dose number.

Table 3 The demographics of vaccinated individuals stratified by vaccine dose number and vaccine brand

Of the 30,281 individuals reporting a vaccine dose, 27,403 (90.5%) reported receiving a first dose, 12,508 (41.3%) reported receiving a first and second dose, and 7891 (26.1%) reported receiving a first, second and third dose. 2878 (9.5%) reported receiving a second or subsequent vaccine dose but did not report details for their first dose. Within the UK COVID-19 vaccine programme, it was recommended that an individual should receive the same vaccine product for their first and second doses (primary course). Of those reporting both primary course doses, 99% reported receiving homologous dose regimens (n = 12,070). Less than 1% of individuals reported receiving a heterogenous course (n = 148). Amongst the individuals who had reported a first dose and received a homogenous schedule, 63.4% (n = 7654) received the AstraZeneca vaccine whilst 34.8% (n = 4203) received the Pfizer vaccine and 1.8% (n = 213) the Moderna vaccine.

3.3 Adverse Reactions Reported Following Vaccination

The demographics for those reporting an ADR are presented in Table 4. 15,764 individuals (52.1%) of those reporting a vaccine dose, reported experiencing at least one ADR following vaccination. The median age of those who reported an ADR was 59 years (IQR: 42–71) and amongst those who did not report an ADR was 68 years (IQR: 49–75). Female individuals more commonly reported ADRs, and the rate of reporting of ADRs decreased with increasing dose number. Demographics of individuals reporting an ADR for each dose stratified by vaccination brand are shown in the table in OSM Resource 3.

Table 4 Number of individuals reporting an adverse drug reaction (ADR) following a COVID-19 vaccination, stratified by demographics and vaccination dose number

Reporters were able to select at least one level of seriousness for their report to describe the impact of an ADR on their lives, although this was non-mandatory. The levels of seriousness indicated by reporters are given in OSM Resource 4. The number of individuals who had reported their ADRs with a level of seriousness was 9,670 (61.3%). These reports were associated with 22,920 events (60.1%). In the cohort of individuals who had reported a first dose in YCVM (n = 14,587), 8,955 (61.4%) reported their ADRs with a level of seriousness. There were 21,484 (60.3%) reactions associated with these reports. For each seriousness category, there was a high proportion of individuals who did not submit a response.

When the reported adverse reactions were categorised as medically serious according to the MedDRA classification, 4134 (13.7% of those reporting any vaccination dose) individuals reported an ADR considered medically serious. A summary table of the demographics for the individuals reporting a MedDRA serious ADR is given in OSM Resource 5.

Amongst the individuals who had reported at least their first dose of vaccination, 14,587 individuals had reported a total of 35,647 ADRs. Figure 2 presents the ADR reporting rates by dose for all ADRs reported and for MedDRA serious ADRs. Records for each dose are included if the individuals reported all previous doses. In addition, one individual reported a single ADR following a sixth dose. 1,093 individuals reported an ADR with no start date, therefore it could not be determined which dose the event followed.

Fig. 2

Average reporting rates of Adverse Drug Reactions (ADRs): Total ADRs and Medical Dictionary for Regulatory Activities (MedDRA) serious ADRs

The ten most prevalently reported ADRs for the first, second and third doses of a COVID-19 vaccination are given for each vaccine brand in OSM Resource 6. Of these ADRs, only arthralgia and myalgia were considered medically serious events according to the MedDRA medical terminology system.

OSM Resource 7 presents the number and proportion of events reported by MedDRA SOC level for each dose and by dose sequence for each vaccine brand. The ADR count listings at MedDRA SOC, HLGT, HLT and PT levels are given in OSM Resource 8.

Due to the approach taken to rollout of the national vaccination campaign to the UK population, analyses of ADR reporting across vaccine brands will potentially be confounded by age and other risk factors for severe outcomes following COVID-19 infection, with the AstraZeneca vaccine being predominantly used in individuals aged 40+ years and those with underlying health conditions and the Moderna vaccine being predominantly used as a third or subsequent dose again in an older population. Age-stratified analyses exploring the ADRs reported in those aged under 40 years and in those aged 40 years or older, presented in OSM Resource 9, do not indicate any particular differences in the ADR reporting patterns between the age groups.

As part of the COVID-19 vaccination surveillance strategy, a list of specific medical events was identified of adverse events of special interest (AESIs) which were subject to enhanced monitoring. In the YCVM, two cases of Guillain-Barre syndrome (GBS) were reported, both with a first dose of the AstraZeneca vaccine. One case of GBS was medically confirmed, while the remaining case was unconfirmed. There were also two cases of transverse myelitis (including ‘myelitis’ events) reported with a first dose of the AstraZeneca vaccine. Information provided was too limited to medically confirm these cases. Finally, there were two cases of Bell’s palsy reported. One occurred after receiving a first dose of the AstraZeneca vaccine but was not medically confirmed. The other case was confirmed by a healthcare professional and occurred after a second-dose vaccination using the Pfizer vaccine.

3.4 COVID-19 Vaccination During Pregnancy and Breastfeeding

At the time of a COVID-19 vaccination, 2,517 females registered on the YCVM platform reported they were pregnant, although only 2,416 provided details of that vaccination. 641 females reported breastfeeding at the time of a COVID-19 vaccination. Demographics of these cohorts and those who experienced an ADR after a vaccination are presented in Table 5. The demographics of females registered, including those with no vaccination reported, are presented in OSM Resource 10.

Table 5 Number of vaccinated individuals reporting an ADR in females, pregnant females, and breastfeeding females registered in the Yellow Card Vaccine Monitor, stratified by demographics

In pregnant females and breastfeeding females reporting a vaccination, the median age was 33 years (IQR: 31–36) and 34 years (IQR: 31–37), respectively. The cohort of vaccinated pregnant females contributed 903.5 patient years follow-up with a median follow-up of 72.5 days (IQR: 5–244).

3.4.1 Pregnant Females

Of the vaccinated pregnant females, 41.2% (n = 995) reported a total of 1934 ADRs in the YCVM. There were 1255 ADRs reported in association with a first dose, 476 with a second dose, 118 with a third dose and three with a fourth dose. There were 82 ADRs with no onset date reported.

Due to the method in which pregnancy status data were collected and stored, it was not always possible to identify which dose or doses were received during pregnancy if they had reported more than one vaccination dose. As a result, all vaccination dose(s) and vaccine brand(s) reported in the YCVM by those who were pregnant are presented here. It does not confirm each reported dose was administered when they were pregnant. 1654 (68.5%) had reported the stage of their pregnancy at the time of vaccination, with 310 reporting more than one stage of pregnancy in which they were vaccinated. The stage of pregnancy reported by these pregnant females and those who also reported at least one ADR are presented in Table 6. The proportion of pregnant females experiencing an ADR after vaccination was similar across the different stages of vaccination during pregnancy.

Table 6 Reported stage of pregnancy during COVID-19 vaccination amongst the cohort of pregnant females

The majority of doses reported by pregnant females were for the first dose of COVID-19 vaccination and the dominant vaccine brand was Pfizer BioNTech (Table 7). Amongst those who had reported a vaccination with AstraZeneca, 116 had reported receiving only one COVID-19 vaccination in their YCVM data and 71 reported at least one ADR. Based on the guidelines that Pfizer or Moderna vaccines were the preferred vaccines for pregnant females, it is more likely these AstraZeneca vaccinations were received prior to them becoming pregnant or when they were unaware they were pregnant during their first trimester. The median number of doses reported in the YCVM by a female who had indicated they were pregnant at the time of a vaccination was one dose (IQR: 1–2 doses). 499 females (20.7%) reported receiving a third dose or booster dose as per guidance, which recommends continued doses should be offered to pregnant females [26].

Table 7 Number of pregnant females registered by brand and dose and (number), [%], who reported an ADR

The most commonly reported ADRs in this cohort for the first, second and third doses of COVID-19 vaccination are given in OSM Resource 11. The reactions reported are common and recognised ADRs associated with vaccines. Pain in extremity, fatigue, headache and pyrexia are the reactions that appear in the top 4 reported ADRs across the three doses.

There were no reports of ADRs in the ‘Congenital, Familial and Genetic Disorders’ SOC. The reports of ADRs belonging to the ‘Pregnancy, Puerperium and Perinatal Conditions’ and ‘Reproductive System and Breast Disorders’ SOCs are presented in Table 8.

Table 8 MedDRA Preferred Terms reported in the ‘Pregnancy, Puerperium and Perinatal Conditions’ and ‘Reproductive System and Breast Disorders’ System Organ Classes (SOC) amongst pregnant females: Number of reactions reported (frequency, % of total number of ADRs) stratified by vaccine brand and dose

There were 26 females who reported an ADR from the ‘Pregnancy, Puerperium and Perinatal Conditions’ SOC, with a total of 28 ADRs reported. Of the total 28 events reported in the ‘Pregnancy, Puerperium and Perinatal Conditions’ SOC category, 13 events (35.7%) were associated with 13 pregnant females who reported receiving a vaccination during their first trimester.

There were 19 reports of spontaneous abortion. The majority of these reports were reported in association with a first dose of COVID-19 vaccination (n = 11), seven with the Pfizer BioNTech vaccine, three with AstraZeneca and one with Moderna. The one case of foetal death was reported alongside a spontaneous abortion, and this was reported in association with a first dose of AstraZeneca. In eight (72.7%) of the reports occurring after a first dose vaccination, the pregnant females had reported vaccination during the first trimester, whilst three reports (27.3%) did not report the trimester in which they were vaccinated. The median time from the last reported vaccination to the reported date of spontaneous abortions occurring after receiving a first-dose vaccination (n = 11) was 27 days (IQR: 18–47 days), and in those occurring after a second-dose vaccination (n = 8) was 33.5 days (IQR: 24–53).

In the ‘Reproductive System and Breast Disorders’ SOC, there were 12 events associated with 12 females who had received a vaccination during their pregnancy. There were four events (33.3%) associated with four pregnant females who reported receiving a vaccination during their first trimester, three in second trimester, two in third trimester, and two with an unknown stage of pregnancy. There was one event reported by a female with multiple stages of pregnancy reported in their YCVM data.

At the time of the pregnant female’s last submission, there were seven events resolved, two recovering, nine ongoing, and ten unknowns in the ‘Pregnancy, Puerperium and Perinatal Conditions’ SOC. In the ‘Reproductive System and Breast Disorders’ SOC, there were seven resolved, two recovering, and three ongoing. The full list of ADRs reported in this cohort of pregnant females and also breastfeeding females is tabulated in OSM Resource 12.

For those who had reported an estimated pregnancy due date, a follow-up was sent 10 weeks after the due date requesting additional information on the outcome of the pregnancy such as full-term births or pre-term births. This information was recorded in the free-text narrative field of the YCVM report. There had been no reports of pre-term births reported as an ADR; however, a search of the free-text field identified four females amongst the vaccinated pregnant females who had reported a premature birth.

3.4.2 Breastfeeding Females

Of the 694 females reported as breastfeeding at the time of a vaccination, 641 had entered details of at least one COVID-19 vaccination; 53.5% (n = 343) of these vaccinated females who were breastfeeding reported a total of 900 ADRs in the YCVM. There were 564 ADRs reported in association with a first dose, 199 with a second dose, 81 with a third dose, and 56 with no onset date. Approximately 64.8% (n = 450) of breastfeeding females and 61.5% (n = 211) of those who went on to report an ADR had reported being vaccinated during their pregnancy.

The information collected on breastfeeding in the YCVM platform was derived from a binary ‘yes’ or ‘no’ question. As a result, where an individual recorded more than one dose, it is not possible to determine at which dose the breastfeeding occurred. The median number of doses reported in the YCVM by an individual who had indicated they were breastfeeding at the time of a vaccination was two doses (IQR: 1–3 doses). At least 235 individuals had reported receiving a third dose or booster dose.

Table 9 presents the number of doses received by individuals by sequence and by brand, during the whole follow-up time in the YCVM. The majority of reported doses were for the first-dose vaccination, with the most frequently reported vaccine brand being the Pfizer vaccine (n = 391).

Table 9 Number of breastfeeding females registered by brand and dose and (number), [%], who reported an ADR

There were no reports of reactions relating to lactation disorders reported in this cohort. There was one report of mastitis occurring after a third-dose vaccination with the Moderna vaccine. In the ‘Pregnancy, Puerperium and Perinatal Conditions’ SOC there was one ADR reported where placental infarction occurred after a first COVID-19 vaccination with the AstraZeneca vaccine. In the ‘Reproductive System and Breast Disorders’ SOC, there were in total six reactions reported with one report of each of the following reactions: irregular menstruation, hypomenorrhea, delayed menstruation, oligomenorrhoea, heavy menstrual bleeding and vaginal haemorrhage. There were no reports of ADRs in the ‘Congenital, Familial and Genetic Disorders’ SOC.

It is possible a female individual may not indicate they were breastfeeding using the optional breastfeeding question. Amongst the ADRs reported by any female individual, there were no reports of lactation related ADRs. However, there were 25 reports of breast disorders – four reports of breast mass, one report of nipple enlargement, one report of breast discharge, 15 reports of breast pain, one report of breast swelling, one report of breast tenderness, and two reports of nipple pain.