3.1. Prescribers
A total of 184 prescribers started with the online questionnaire, and after exclusion, a total of 90 prescribers were included in the study. Reasons for exclusion were not obtaining informed consent, not answering any question at all, not being a physician, and never having prescribed valproate (
Figure S1).
The mean age was 51 years old with a small majority being female (
Table 2). Most of the prescribers were medical specialists and, in particular, neurologists (
Table 2). A majority had been practicing in their current field for 11 years or more and consulted once a month or less with women of reproductive age who took valproate (
Table 2).
A majority of the prescribers (95.6%, n = 86) were aware of the teratogenic effects of valproate; 73.3% (n = 66) had heard about the effects more than 5 years ago (
Supplementary Table S1). More than half of the prescribers (54.7%, n = 47) obtained this information from colleagues, 47.7% (n = 41) from professional societies, and 44.2% (n = 38) from symposia/conferences (
Supplementary Table S2). Professional societies (
p = 0.006), colleagues (
p = 0.001), and symposia/conferences (
p = 0.002) more often provided information to medical specialists compared to GPs. Only one GP mentioned professional societies and colleagues, and no GP mentioned symposia/conferences as an information source.
The patient guide was the most used material (27.8%) by prescribers, followed by the HCP guide (23.3%), and the DHPC letter (23.3%) (
Table 3). In addition, the majority who did not apply the PPP measures at all mentioned these three measures as most likely to be used in the future (
Table 3). The most unlikely measures to be used in the future were signing (32.9%) and reviewing (30.3%) the risk acknowledgment form (RAF) and applying the patient reminder card (30.3%) (
Table 3). Based on the analysis of the open-ended questions, the low use of the RAF was due to lack of awareness of its existence and the opinion that there was no need for reading and signing it if the patient was informed and had already given verbal consent to the treatment.
Regarding the current practice of valproate prescribing, a majority agreed with not prescribing valproate to women of reproductive age at all or being selective when prescribing it to women of reproductive age (
Table 4). More medical specialists than GPs agreed on being selective (
p < 0.001), while half of the GPs stated that being selective was not relevant for them. Pregnancy testing before starting with valproate treatment was the most common (24.4%) in comparison to testing during (10.0%) and after (6.7%) treatment of valproate (
Table 4). Medical specialists informed women more often about the importance of contraception while using valproate compared to GPs (
p = 0.024), with half of the GPs stating that this was not relevant for them. On the other hand, prescribing contraception to women who took valproate was more often found among GPs; 78.6% (n = 11) of the GPs and 20% (n = 15) of the medical specialists stated that they are prescribing contraception. A sizeable proportion of the medical specialists (40%, n = 30) reported that the latter was not relevant for them (
p < 0.001).
Finally, 35.5% (n = 32) of the prescribers stated that their prescribing and counselling of women of reproductive age who took valproate did not change, and 26.7% (n = 24) stated that it did change since the implementation of the PPP for valproate in 2018 (
Supplementary Table S3). Among those who stated that prescribing and counselling did change, the majority thought that the HCP guide had the most impact (50%, n = 12), followed by the DHPC (37.5%, n = 9) (
Supplementary Table S4). The patient reminder card and signing the RAF had the least impact (16.7%, n = 4) (
Supplementary Table S4). Based on the analysis of the open-ended questions, lack of time was the most frequently mentioned barrier for prescribers for the implementation and/or use of the pregnancy prevention measures. Participants stated that handling the letters, guides, patient cards, and risk forms consume time, with the consequence that less time is available for the patient and the doctor to have a conversation about the treatment and its consequences. A lack of awareness, availability, and easy access to the materials were other mentioned barriers. The prescribers suggested that all the materials should be accessible online.
3.2. Pharmacists
A total of 149 pharmacists started with the online questionnaire, and after exclusion, a total of 98 pharmacists were included in the study. Reasons for exclusion were not obtaining informed consent, not answering any question at all, not being a pharmacist, and never having dispensed valproate (
Figure S2). Pharmacists’ mean age was 39 years old with a majority being female (
Table 5). Most were community pharmacists (88.8%), and the remaining were hospital pharmacists (
Table 5). More than half of the pharmacists had practiced in their current profession for 0–5 years. The majority dispensed valproate and provided information about valproate to women of reproductive age once a month or less. It was noteworthy that 20.4% (n = 20) of the pharmacists never provided information to women of reproductive age about valproate.
A majority of the pharmacists (78.6%, n = 77) were aware of the teratogenicity of valproate; 51% (n = 50) had heard about the effects in the past 5 years (
Supplementary Table S5). A percentage of 15.3% (n = 15) were unaware and learned about the teratogenic effects of valproate when answering the questionnaire. Academic studies (46.8%, n = 36), the Danish Medicines Agency (33.8%, n = 26), and manufacturers (31.2%, n = 24), were the most often mentioned sources for obtaining information about the teratogenicity of valproate (
Supplementary Table S6).
The use of the warning sign on the outer medication package was the most applied pregnancy prevention measure for pharmacists (
Table 6). However, a majority of the pharmacists stated they had never used it or were not sure if they had used it. Some 79% (n = 49) stated they would be likely to use the warning sign on the medication package in the future (
Table 6). The patient reminder card and the HCP guide were the least used (
Table 6). Based on the analysis of the open-ended questions, pharmacists referred to a lack of availability and/or awareness of these measures. While dispensing valproate, pharmacists most often provided information about the importance of effective contraception and advised patients to contact their prescriber if they suspected a woman of being pregnant (
Table 7). On the other hand, a majority of the pharmacist never or seldom advised patients to stop taking valproate if they suspected a woman to be pregnant and never or seldom highlight the importance of testing for pregnancy before and during the treatment (
Table 7).
Some 27.6% (n = 27) of the pharmacists were not sure if the information they provided to women of reproductive age when dispensing valproate had changed since the implementation of the PPP for valproate in 2018 (
Supplementary Table S7). The pharmacists who had practiced their profession for the shortest time (0–5 years) reported the change (17.0%, n = 9) less often compared to the pharmacists with more than 20 practicing years (36.4%, n = 4) (
p = 0.027). For the 24.5% (n = 24) of pharmacists who said their dispensing of valproate changed, the warning sign on the outer packaging and the DHPC had the highest impact on their valproate dispensing practices (
Supplementary Table S8). In the answers to the open-ended questions, pharmacists expressed that the warning sign helped to recall instructions when dispensing valproate. Lack of time and insufficient knowledge of PPP were most often mentioned as barriers to the implementation of the measures aside from the insufficient integration of these measures into the daily workflow. In addition, discussing the topic of pregnancy was often seen as a private matter, which could be unsuitable to discuss at the pharmacy counter. Patient-related hindrances for the implementation of the measures, raised by the pharmacists, were the unwillingness of patients to listen to the advice provided and that at times someone else rather than the actual medicine user picks up the medication at the pharmacy. As improvements, pharmacists would like to see the implementation of a warning in the electronic dispensing system, which will pop-up when valproate is dispensed. On top of that, they stated that more campaigns should be created to repeat and highlight the important information about the PPP in relation to valproate dispensing.
3.3. Patients
A total of 236 patients started with the online questionnaire, and after exclusion, a total of 103 patients were included in the study. Reasons for exclusion were not obtaining informed consent; not answering any question at all; not reporting gender, date of birth or pregnancy status; being pregnant; and never using valproate (
Figure S3).
The mean age of patients was 38 years old, and the most common level of education was university at undergraduate level (
Table 8). The majority (48.5%) had never been pregnant, and for the women who had, 51.2% used valproate during their pregnancy (
Table 8). For the patients who used birth control, the majority used birth control pills or an intrauterine device (IUD) (
Table 8).
The awareness about the teratogenic effects of valproate among responding women was high (81.6%, n = 84) (
Supplementary Table S9). Of these women, 63.1% (n = 53) obtained the information via their neurologist, 26.2% (n = 22) via the patient information leaflet (PIL), 16.7% (n = 14) from the Internet, and 15.5% (n = 13) via their GP (
Supplementary Table S10). A majority of 40.0% (n = 16) stated that they were not particularly careful, and 27.5% (n = 11) stated that they were particularly careful to use pregnancy prevention while taking valproate. Of the eleven patients who were careful, seven were from the age group of 20–30 years old. In the youngest age group (16–20 years old), no one agreed to be particularly careful regarding birth control during valproate use (
p < 0.001).
A large share (74.8%, n = 77) of the patients had read the PIL included in the medication package; 23.3.% (n = 24) discussed the use of contraception to prevent pregnancy with a neurologist or GP; only 1.9% (n = 2) and 2.9% (n = 3), respectively, signed and reviewed the RAF, and 1.9% (n = 2) received a patient reminder card (
Table 9). The frequency of pregnancy testing during the use of valproate was low. Before and after the treatment with valproate, three patients stated they took a pregnancy test (2.9%), and during the treatment with valproate seven patients (6.8%) regularly took a pregnancy test (
Table 9). In the group of 30–40 years old and the youngest age group (16–20 years old), no one ever took a pregnancy test (
p = 0.038). Based on the analysis of the open-ended questions, taking a pregnancy test was not relevant for the latter age group because they were not sexually active, making it unlikely and/or impossible to become pregnant.
For most of the patients, the use of their medication containing valproate did not change since the implementation of the PPP in 2018. Some 40.8% (n = 42) stated that they use valproate in the same way as in 2018 or earlier, and 33% (n = 34) could not tell if their use of valproate changed because they stopped the medication before 2018 (
Supplementary Table S11).