The safety of medicines and vaccines continues to be monitored after they are introduced for use, but unfortunately not all side effects are captured in registries or medical records. A recently published study provides a more comprehensive picture of these side effects and opens up new opportunities to investigate their underlying causes.
Previous studies have shown that people may experience unpleasant symptoms that are not formally noted in their health records. To help close this gap, researchers at the University of Tartu developed a questionnaire on medicine- and vaccine-related side effects, which was completed by nearly 46,000 participants of the Estonian Biobank. More than 13,000 respondents reported side effects associated with medicines, and nearly 16,000 reported side effects associated with vaccines.
This results in one of the largest datasets of its kind, helping researchers better understand patient experiences and challenges related to the use of medicines and vaccines. The large number of respondents also supports the study of rare and more serious side effects that are difficult to detect in smaller studies.
Linking participants’ responses with genetic and health data from the Estonian Biobank allows us to investigate the genetic basis of side effects,” said Lili Milani, Professor of Pharmacogenomics and lead investigator of the study. “This helps us understand why the same medicine causes side effects in some people while others tolerate it well. The size of the dataset, for example, enabled us to identify a genetic variant associated with an increased risk of vaccine-related side effects.
Side Effects are Common and Often Influence Treatment Adherence
The collected data confirm that side effects are far from uncommon. 29 percent of questionnaire respondents, more than one in four people, reported experiencing side effects from medicines. Women reported side effects considerably more often than men. The most frequently mentioned medicines were the antibiotics penicillin and amoxicillin, with skin rash being the most commonly reported side effect.
Approximately 35 percent of all respondents reported vaccine-related side effects, the majority of which were associated with COVID-19 vaccines. “This is not surprising, as data collection took place after population-wide COVID-19 vaccinations. It is also likely that individuals who experienced side effects were more motivated to participate in the survey,” said Milani.
Side effects often influence whether people continue treatment. “Our results show that a side effect is not always just a temporary inconvenience. It may also lead people to discontinue necessary treatment. Both experienced side effects and concerns about them can affect treatment decisions,” said Kristi Krebs, Research Fellow in Pharmacogenomics and lead author of the study.
Among respondents who reported side effects from a medicine, about half discontinued treatment entirely, while one-third were switched to an alternative medication. In some cases, reading the package leaflet alone was enough to discourage treatment. 13 percent of respondents had either decided not to start treatment or stopped prematurely because of side effects described in the leaflet.
Self-Reported Experiences Align with Health Records
To assess the reliability of the questionnaire data, researchers compared some responses with data from electronic health records. For example, 95 percent of women who reported changing their contraceptive method because of side effects had indeed done so according to prescription records. A similar pattern emerged for blood pressure medications. Respondents who reported changing or discontinuing treatment due to side effects were significantly more likely to exhibit the same behaviour according to prescription data than other participants.
These findings suggest that people’s own reports reflect real-world experiences and provide valuable complementary information. In particular, they help identify side effects that may never be recorded in medical records. Well-known side effects reported in the questionnaire also matched established clinical knowledge. For example, muscle pain was commonly reported with cholesterol-lowering medications, while digestive problems were frequently reported with the diabetes medication metformin.
The researchers emphasise, however, that self-reported experiences do not prove that a medicine or vaccine caused a particular symptom. They do, nevertheless, provide an important starting point for further investigation.
The Impact of Medicines and Vaccines on the Menstrual Cycle
One of the most novel aspects of the study was its focus on menstrual cycle changes associated with medicines and vaccines. Such information has previously been very limited, but researchers were now able to examine the experiences of more than a thousand women.
Following vaccination, women most commonly reported longer intervals between periods, heavier bleeding, and longer-lasting menstruation. The majority of reports were related to COVID-19 vaccines, and most of the changes were temporary.
Medicine-related changes were also generally temporary, but often showed opposite patterns. Women most frequently reported lighter bleeding and shorter periods. Many of these cases were linked to hormonal contraceptives. In many instances, these changes reflected the expected effects of the contraceptives but were nevertheless perceived by respondents as side effects.
According to Triin Laisk, Professor of Genomic Epidemiology at the University of Tartu, this is among the first large-scale efforts to systematically collect data on menstrual cycle changes associated with medicines and vaccines. The findings contribute to understanding an area that has received relatively little attention in drug safety research.
Genes Help Explain Why Side Effects Occur
Linking questionnaire responses with genetic data has already produced important findings. For example, researchers have shown that people who metabolise certain antidepressants more slowly because of variants in the CYP2C19 gene are more likely to experience side effects. They have also demonstrated that several side effects more commonly reported after the Pfizer COVID-19 vaccine, including headache, nausea and heart palpitations, are associated with a specific genetic variant influencing the immune system. This finding supports the results of a previous study conducted in the USA where the same HLA allele was associated with more frequent reports of fever, chills and fatigue from Pfizer vaccines. Although the two studies examined slightly different side effects, both point to a stronger immune response as a possible explanation.
The dataset also enabled researchers to confirm the role of genetic factors in side effects observed with blood pressure medications. For example, the well-known side effect of dry cough among users of ACE inhibitors was up to twice as common among individuals with the highest genetic risk compared to others.
Thanks to the thousands of biobank participants who shared their experiences, researchers are gaining a better understanding of which genetic variants are associated with side effects of specific medicines and vaccines. In the future, such knowledge could help guide the selection of treatments and doses that are both effective and as safe as possible for each individual.
The results of the questionnaire are described in greater detail in an article published in the International Journal of Epidemiology .
International Journal of Epidemiology
Meta-analysis
People
Cohort Profile Update: The Adverse Events Questionnaire of Medications and Vaccines (ADE-Q) in the Estonian Biobank
14-Oct-2026