Original Article
Adverse reactions to human papillomavirus vaccine in the Valencian Community (2007–2011)
Notificación de reacciones adversas a la vacuna frente al virus del papiloma humano en la Comunidad Valenciana (2007–2011)
M.A. Rodríguez-Galána,
, S. Pérez-Vilara, J. Díez-Domingoa, J. Tuellsb, J. Gomar-Fayosc, F. Morales-Olivasd, E. Pastor-Villalbae
Corresponding author
a Área de Investigación en Vacunas, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana FISABIO – Salud Pública, Valencia, Spain
b Cátedra de Vacunología Balmis UA-FISABIO, Universidad de Alicante, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana FISABIO – Salud Pública, Valencia, Spain
c Centro Autonómico de Farmacovigilancia de la Comunidad Valenciana, Dirección General de Farmacia y Productos Sanitarios, Conselleria de Sanitat, Valencia, Spain
d Departamento de Farmacología, Universidad de Valencia, Valencia, Spain
e Unidad de Coordinación y Promoción de la Salud, Dirección General de Salud Pública, Conselleria de Sanitat, Valencia, Spain
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"apellidos" => "Pastor-Villalba" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Área de Investigación en Vacunas, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana FISABIO – Salud Pública, Valencia, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Cátedra de Vacunología Balmis UA-FISABIO, Universidad de Alicante, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana FISABIO – Salud Pública, Valencia, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Centro Autonómico de Farmacovigilancia de la Comunidad Valenciana, Dirección General de Farmacia y Productos Sanitarios, Conselleria de Sanitat, Valencia, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Departamento de Farmacología, Universidad de Valencia, Valencia, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Unidad de Coordinación y Promoción de la Salud, Dirección General de Salud Pública, Conselleria de Sanitat, Valencia, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Notificación de reacciones adversas a la vacuna frente al virus del papiloma humano en la Comunidad Valenciana (2007–2011)" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1270 "Ancho" => 2165 "Tamanyo" => 159320 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Number of adverse reaction reports linked to the administration of the quadrivalent HPV vaccine in girls aged 13–15 years received by the Centro Autonómico de Farmacovigilancia de la Comunidad Valenciana.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The vaccine against human papillomavirus (HPV) is indicated for the prevention of cervical cancer and precancerous lesions of the female genital tract.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> There are 2 approved vaccines: Cervarix<span class="elsevierStyleSup">®</span>, a bivalent vaccine that covers HPV types 16 and 18, and Gardasil<span class="elsevierStyleSup">®</span>, a tetravalent vaccine that covers HPV types 6, 11, 16 and 18.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Prior to the approval of both vaccines, clinical trials demonstrated their safety and efficacy in the prevention of precancerous lesions. The adverse effects reported most frequently were pain, redness, and swelling at the site of injection, headache, myalgia, and fatigue.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–6</span></a> After the administration of approximately 56 million doses, the <span class="elsevierStyleItalic">Vaccine Adverse Events Reporting System</span> (VAERS), the passive surveillance system of the United States, received a total of 21,194 reports in relation to the quadrivalent HPV vaccine, and the most commonly reported adverse events were syncope, dizziness, nausea, headache, fever, and urticaria, injection-site reactions (pain, redness, and swelling).<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The administration of the quadrivalent vaccine has also been associated to mass psychogenic response in adolescents,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> as happens with other vaccines,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> with symptoms including dizziness, syncope, and neurological complaints without an identified organic cause.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In the case of the bivalent preparation, after the administration of 558,226 doses, 647 adverse events were reported to the <span class="elsevierStyleItalic">National Institute for Public Health and the Environment</span> (RIVM) in the Netherlands, and the adverse events reported most frequently were local reactions, general skin symptoms, syncope, and presyncope.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Both vaccines were introduced in the Spanish market in September 2007.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The vaccine against HPV was included in the routine immunisation schedule of the Autonomous Community of Valencia in October 2008 to be administered in schools or healthcare centres to girls aged 14 years.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In February 2009, a lot of media coverage was given to reports of seizures in 2 girls following the administration of the second dose of the quadrivalent vaccine in close geographical and temporal proximity.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> As an immediate precaution, the Spanish authorities suspended vaccination with the batch concerned in the seizure cases, and the Valencian Community restricted the administration of HPV vaccines to healthcare centres.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> Both the Agencia Española de Medicamentos y Productos Sanitarios (Spanish Agency of Drugs and Health Products [AEMPS]) and the European Medicines Agency (EMA) assessed both cases and determined that they had not been caused by the vaccine.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,16</span></a> Furthermore, the EMA concluded that the benefits of the vaccine continued to outweigh its risks, and recommended reinforcing the product information on the possibility of syncope, sometimes accompanied by tonic–clonic movements resembling seizures, as a side effect of vaccination with Gardasil.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> On the other hand, a study conducted by the Center for Disease Control (CDC) of the United States determined that there was no increase in the risk of syncope following administration of the quadrivalent HPV compared with other vaccines administered during adolescence.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Despite the educational efforts of healthcare authorities, vaccination coverage continues to be lower than expected. Coverage rates of HPV vaccination coverage were 65% in Spain and 58% in the Autonomous Community of Valencia,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> although the rates have recovered in part in the cohort of girls born between 1995, 1996, and 1997 and vaccinated in 2009, 2010, and 2011.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Passive surveillance in Spain is carried out through the programme for the spontaneous reporting of suspected adverse reactions (SARs) to medicines of the Sistema Español de Farmacovigilancia (Spanish Pharmacovigilance System [SEFV]). Healthcare professionals report suspected events by means of a form known as the “yellow card.” Also, the Autonomous Community of Valencia has a Registro Nominal de Vacunas (Nominal Vaccination Registry [RVN]),<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> a system that records the vaccinations given in all public and some private facilities, which also allows electronic reporting of SARs to vaccines to the Centro Autonómico de Farmacovigilancia de la Comunidad Valenciana (Pharmacovigilance Centre of the Valencian Community [CAFCV]).</p><p id="par0030" class="elsevierStylePara elsevierViewall">The aim of this study was to describe the SARs to the HPV vaccine reported to the CAFCV, and to compare the reporting rates for syncope and seizures linked to this vaccine with the reporting rates for the rest of the vaccines administered to girls 13–15 years of age.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">We conducted a descriptive retrospective study by analysing the SARs to the HPV vaccine reported by healthcare professionals to the CAFCV between September 2007 and December 2011.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The study included reports concerning girls aged 13–15 years that had the minimum information required for processing, as determined by the SEFV criteria.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The reporting rates for syncope, presyncope, and seizures for the HPV vaccine and the rest of the vaccines administered in girls 13–15 years of age (meningococcal C conjugate vaccine, conjugate meningococcal C, tetanus toxoid, varicella, and tetanus diphtheria [Td] vaccines) calculated by dividing the number of reports for each clinical manifestation by the number of administered doses registered in the RVN; we calculated the 95% confidence intervals (95% CI) by the Clopper–Pearson method.</p><p id="par0050" class="elsevierStylePara elsevierViewall">After grouping the SARs by clinical manifestation, we performed a descriptive analysis of the variables using SPSS version 19.0.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">The CAFCV received a total of 200 SRA reports. All reports concerned the quadrivalent HPV vaccine, which was the preparation administered in the Valencian Community in the period under study. The study only included 194 of the reports, as the remaining 6 (3%) did not include the date the vaccine was administered, a datum needed to establish a temporal relationship with the clinical manifestations reported. The records of the RVN indicate that 187,385 doses of the vaccine were administered in the same time period, so these 194 reports correspond to a reporting rate of 103 reports (95% CI, 89–118) per 100,000 administered doses.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Description of the analysed reports</span><p id="par0060" class="elsevierStylePara elsevierViewall">Of the 194 reports included in the study, 4 (2%) corresponded to girls aged 13 years, 158 (81%) to girls aged 14 years, and 32 (16.5%) to girls aged 15 years.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The number of reports was 33 (17%) in 2008, 106 (55%) in 2009, 42 (21.6%) in 2010, and 13 (6.7%) in 2011. There were no reports of SARs in 2007 (September–December). The number of reports per month increased after the introduction of routine vaccination, from none in October 2008 to 23 the following month. The other 2 peaks in reporting coincided with the administration of the second and third doses to the first cohort of vaccinated girls (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Of all reports, 149 (77%) involved systemic clinical manifestations alone, and 22 (11%) local reactions. The remaining 23 (12%) reported both systemic and local manifestations. The staff of the CAFCV classified 32% of the reports as serious based on the criteria set by the SEFV.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The 194 reports included 433 SRAs, with an average of 2.2 clinical manifestations by report, and a range of 1–14. The adverse events reported most frequently were dizziness (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>52; 27%), headache (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>44; 23%), syncope or loss of consciousness (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>38; 20%), and fever (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>32; 17%). Reactions reported less frequently included pain at the injection site (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>19; 10%), nausea (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>15; 8%), vomiting, pallor, general malaise (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>12, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11, and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11, respectively; 6%), somnolence (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10; 5%), presyncope (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8; 4%), and seizures (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6; 3%).</p><p id="par0080" class="elsevierStylePara elsevierViewall">Syncope or loss of consciousness was described in 38 of the reports (20%). It was accompanied by seizures in 6 cases, which we described separately for that reason. Of the remaining 32 reports, 14 were of syncope or loss of consciousness alone, and 18 of syncope or loss of consciousness in combination with other clinical manifestations, the most frequent of which were dizziness,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> pallor,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> hypotension,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and vomiting.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> One report also informed of syncope combined with a concussion, and another of syncope in combination with muscle spasms. The episodes of syncope took place on the day of vaccination in 28 out of the 32 reports; in the remaining 4 the latency period lasted between 2 and 10 days, with the episode occurring at a median of 2.5 days postvaccination. The reporting rate for syncope or loss of consciousness was 17 (95% CI, 11.1–23) per 100,000 administered doses, and the rate for syncope occurring on the day of vaccination was 15 (95% CI, 9.4–20.4) per 100,000 administered doses.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Presyncope was described in 8 reports (4%). In 2 of them it was reported by itself and in another 2 along with syncope. In the remaining 4, it was reported with pain in 1, with dizziness in another, and with general malaise in 2. In all 6 reported cases of presyncope (having excluded those in which syncope was reported simultaneously), the onset occurred on the day of vaccination. The reporting rate for presyncope was 3.2 (95% CI, 0.6–5.7) per 100,000 administered doses.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Seizures were described in 6 reports (3%). They were associated to syncope in 4, of which 2 described syncope and seizures (specified as grand mal seizure in one case) as the only two clinical manifestations. Another report described seizures in combination with muscle stiffness, and the last one in combination with motor disturbances (myoclonus and hypertonia). The onset of seizures occurred on the day of vaccination in 5 of the 6 reports, and only occurred later in 1, corresponding to the grand mal seizure, at 50 days postvaccination. The reporting rates per 100,000 administered doses were 3.2 for seizures (95% CI, 0.6–5.7), 2.1 for syncopal seizure (95% CI, 0.04–4.2), and 1.6 for syncopal seizure on the day of vaccination (95% CI, −0.2 to 3.4).</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the period under study, a total of 248,677 doses of vaccines other than the HPV vaccine were administered to girls aged 13–15 years in the Valencian Community, giving rise to 27 reports. Of these, 16 described syncope or loss of consciousness; 6, presyncope; and 1, seizures. The reporting rates for these clinical manifestations were 6.4 (95% CI, 3.2–9.5), 2.4 (95% CI, 0.4–4.3), and 0.4 (95% CI, −0.3 to 1.1) reports per 100,000 administered doses, respectively (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0100" class="elsevierStylePara elsevierViewall">The clinical manifestations reported to the CAFCV are consistent with those described in the summary of product characteristics<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and those reported by passive surveillance systems following licensure.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,21</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The reporting rate of SARs linked to the quadrivalent HPV vaccine in the Valencian Community is higher than the one reported by VAERS in the United States for the same vaccine<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Researchers in the Netherlands considered that the media controversy surrounding the vaccine had an effect on the reporting rate.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The heavy media coverage of the introduction of the vaccine in the routine vaccination schedule and the seizure episodes suspected to be linked to the vaccine in 2009 may have led to an increased reporting rate in the Valencian Community, too. This is a known effect that is manifested when a pharmacological agent is subject to media exposure, be it because there is a well-known association to a reaction, or because regulatory authorities have issued a warning.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Still, we must take into account that for the period under study, reports with the CAFCV were only filed by healthcare professionals, while in the VAERS and RIVM systems anyone can make a report.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,23</span></a> The RIVM also uses an actively stimulated surveillance system.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Furthermore, the reporting rate of SARs linked to the quadrivalent HPV vaccine was greater than the rate observed for vaccines that have been administered to adolescents in the Valencian Community for years (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). This could be explained by the Weber effect, which describes an increased number of reports to passive surveillance systems in the early years post-licensure.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,26</span></a> This hypothesis would be supported by the findings represented in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, which shows a larger number of reports coinciding with the administration of the 3 doses of the vaccine the first year it was included in the routine schedule,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> with a decline in the second year.</p><p id="par0115" class="elsevierStylePara elsevierViewall">The reporting rates for events linked to the HPV vaccine or other vaccines were calculated without consideration of the issue of polyvaccination, so the rates attributable to the HPV vaccine could be lower than the ones obtained. Furthermore, the reporting rates described in other studies<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21,27</span></a> were not calculated for a specific age group, as we did, and they used the number of distributed doses in the calculations, rather than the number of administered doses which we used.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Syncope or loss of consciousness were the clinical manifestations reported most often to the CAFCV, consistent with the reports to the VAERS and RIVM.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,21</span></a> However, the reporting rate both for syncope or loss of consciousness on the day of vaccination and for the total cases of syncope or loss of consciousness was greater than the rates found by other passive surveillance systems,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and greater than the rates for other vaccines administered to adolescents in the Valencian Community (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). This could also be accounted for by the effects previously described; intense media coverage was followed by the healthcare authorities suggesting the reinforcement of information pertaining to administration of this vaccine and the onset of syncope, at times accompanied by tonic-clonic movements similar to seizures, which may have stimulated a higher number of reports of these clinical manifestations. Another factor to consider is that syncope secondary to vaccination tends to happen within 15<span class="elsevierStyleHsp" style=""></span>min following administration of the vaccine.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> However, since we did not have detailed information on the time elapsed, our calculation of the rates of syncope or loss of consciousness included all cases that occurred on the day of vaccination, so we may have overestimated them.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Concussion was reported along with syncope only once. Other studies have shown greater reporting rates for injuries due to the falls that followed the syncope.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21,28</span></a> This difference could be explained by the underreporting inherent in passive surveillance systems, although injuries resulting from syncope tend to be considered serious and should consequently be reported. It could also be explained by adequate management of the postvaccination period. Following the convulsion cases reported in 2009, administration of this vaccine was restricted to healthcare centres in the Valencian Community, and these types of events are more likely to be prevented in those settings.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The reporting rate for presyncope linked to the HPV vaccine was greater than the rate associated with other vaccines administered to adolescents, but we did not find studies assessing the reporting rates for this clinical manifestation. This may be due to nonreporting of mild clinical manifestations, especially for pharmacological agents that have not been licensed recently.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The reporting rate for seizures was higher than that of the VAERS<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and higher than the reporting rate for other vaccines administered in adolescence (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). This, too, could be explained by the impact of the media coverage of the seizures suspected to be linked to the vaccine in Valencia, and by the Weber effect. Since we did not have access to medical histories, all reports that informed of both seizures and syncope were classified as syncopal seizures. The reporting rate for syncopal seizure on the day of vaccination thus calculated was lower than the one published in a previous study,<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> although the latter was based on a stimulated reporting system.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Pharmacovigilance uses a variety of quantitative methods to evaluate the association between pharmacological agents and their possible adverse effects based on searching the databases for statistical disproportions to determine whether a reaction is reported more frequently for one agent than for others. One such method is the <span class="elsevierStyleItalic">reported odds-ratio</span> (ROR), which consists of a study of cases and controls in which the controls, referred to as non-cases, are reported adverse reactions other than the one under study.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Calculating the ROR for syncope, presyncope, and convulsions was not useful in this study because the number of non-cases was very small, with most such clinical manifestations reported in girls aged 13–15 years being linked to vaccination against HPV (27 reports for other vaccines vs 194 reports for the HPV vaccine).</p><p id="par0145" class="elsevierStylePara elsevierViewall">There are limitations to this study. One is that in any system of passive surveillance, there is a higher reporting rate for newly approved agents (Weber effect), and a tendency to underreport well-known adverse reactions for agents that have been licensed for longer periods of time. On the other hand, these systems are very sensitive to the effects of media attention. Also, missing data in the reports and the unavailability of medical histories make reported events difficult to confirm. A temporal association between the administration of a given agent and a reported adverse reaction is not enough to establish causality.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Nevertheless, our results confirm that none of the reported clinical manifestations diverged from those described in the summary of product characteristics of the vaccine and those reported in another passive surveillance system.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,21</span></a> They also provide information about the convulsions and syncope that have been the subject of public debate, suggesting a potential correlation between media attention and reporting rates.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres381377" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Materials and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec360156" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres381376" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec360155" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Description of the analysed reports" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-08-07" "fechaAceptado" => "2013-11-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec360156" "palabras" => array:5 [ 0 => "Adverse reactions" 1 => "Vaccine" 2 => "Human papillomavirus" 3 => "Pharmacovigilance" 4 => "Reporting rate" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec360155" "palabras" => array:5 [ 0 => "Reacción adversa" 1 => "Vacuna" 2 => "Virus del papiloma humano" 3 => "Farmacovigilancia" 4 => "Tasa de notificación" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">In 2009, two cases of seizures in adolescents following quadrivalent human papillomavirus vaccine (qHPV) administration generated important media attention, and adversely affected public trust in this vaccine. Our objectives were to describe suspected adverse reactions (SARs) reported to the Pharmacovigilance Centre in the Valencian Community (PCVC) after administration of HPV vaccine, and to compare reporting rates of syncope and seizures following this vaccine with those of other vaccines administered to girls aged 13–15<span class="elsevierStyleHsp" style=""></span>years.</p> <span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Descriptive study of SARs reported following administration of this vaccine to the PCVC between 2007 and 2011.</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The clinical symptoms most frequently reported were dizziness, headache, and syncope.</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Reporting rates of syncope or loss of consciousness and seizures with qHPV vaccine were 17 and 3.2 per 100,000 doses administered, respectively, and 15 and 1.6 for syncope or loss of consciousness and syncopal seizures occurred on the day of vaccination. The reporting rates of syncope or loss of consciousness and seizures were 6.4 and 0.4, for the other vaccines.</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Consistent with the media attention generated, and with results from other studies, the reporting rates of syncope or loss of consciousness and seizures were higher for the HPV vaccine than for other vaccines given in adolescence. Nevertheless, the overall information obtained on SARs following the qHPV vaccine suggests a good safety profile.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">En 2009, 2 casos de convulsiones en adolescentes tras la administración de la vacuna tetravalente frente al virus del papiloma humano (VPH) generaron impacto mediático y afectaron negativamente la confianza del público en esta vacuna.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Nuestros objetivos fueron describir las sospechas de reacciones adversas (SRA) notificadas al Centro Autonómico de Farmacovigilancia de la Comunidad Valenciana (CAFCV) tras la administración de la vacuna frente al VPH y comparar la tasa de notificación de síncope y convulsiones de esta vacuna con la de otras vacunas administradas en adolescentes.</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Estudio descriptivo de las notificaciones de SRA relacionadas con esta vacuna recibidas por el CAFCV entre 2007 y 2011.</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Las manifestaciones clínicas más comunicadas fueron mareos, cefalea y síncope.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Las tasas de notificación de síncope o pérdida de conciencia y convulsiones con la vacuna frente al VPH fueron de 17 y 3,2 por 100.000 dosis administradas, respectivamente, y de 15 y 1,6 para síncope o pérdida de conciencia y convulsiones sincopales ocurridas el día de la vacunación. Las tasas de notificación de síncope o pérdida de conciencia y convulsiones fueron de 6,4 y 0,4 para otras vacunas.</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Las tasas de notificación de síncope o pérdida de conciencia y convulsiones fueron mayores para la vacuna frente al VPH que para otras vacunas administradas en adolescentes; esto es consistente con la atención mediática originada por la vacuna y con hallazgos de estudios previos. No obstante, la información obtenida sobre las SRA a la vacuna sugiere un buen perfil de seguridad.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as: Rodríguez-Galán MA, Pérez-Vilar S, Díez-Domingo J, Tuells J, Gomar-Fayos J, Morales-Olivas F, et al. Notificación de reacciones adversas a la vacuna frente al virus del papiloma humano en la Comunidad Valenciana (2007–2011). An Pediatr (Barc). 2014;81:303–309.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1270 "Ancho" => 2165 "Tamanyo" => 159320 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Number of adverse reaction reports linked to the administration of the quadrivalent HPV vaccine in girls aged 13–15 years received by the Centro Autonómico de Farmacovigilancia de la Comunidad Valenciana.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">HPV: vaccine against human papillomavirus.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Clinical manifestation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Observed reporting rate: quadrivalent HPV vaccine<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> (95% CI) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Expected reporting rate: other HPV vaccine studies<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Observed reporting rate: other vaccines<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> (95% CI) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Syncope or loss of consciousness \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 (11.1–23) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.8<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>/8.2<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.4 (3.2–9.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Syncope or loss of consciousness on vaccination day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (9.4–20.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presyncope \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.2<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> (0.6–5.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.4 (0.4–4.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Seizures \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.2 (0.6–5.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.3<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.4 (−0.3 to 1.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Syncopal seizures \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.1 (0.04–4.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Syncopal seizures on vaccination day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.6 (−0.2 to 3.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.6<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">103 (89–118) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53.9<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>/116<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.8 (6.7–14.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab581265.png" ] ] ] "notaPie" => array:5 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Reports per 100,000 administered doses.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Reports per 100,000 distributed doses.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">All the presyncopes occurred on the day of vaccination.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Reporting rate for serious seizures.</p>" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Reporting rate for the bivalent HPV vaccine per 100,000 administered doses.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Reporting rates observed in the Valencian Community for the HPV vaccine, reporting rates for the HPV vaccine published in other post-licensure studies, and reporting rates for other vaccines observed in the Valencian Community.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Calendario de vacunaciones de la Asociación Española de Pediatría: recomendaciones 2011" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 10 | 19 |
| 2024 October | 49 | 33 | 82 |
| 2024 September | 52 | 37 | 89 |
| 2024 August | 53 | 52 | 105 |
| 2024 July | 43 | 44 | 87 |
| 2024 June | 54 | 35 | 89 |
| 2024 May | 50 | 46 | 96 |
| 2024 April | 51 | 33 | 84 |
| 2024 March | 51 | 30 | 81 |
| 2024 February | 46 | 37 | 83 |
| 2024 January | 29 | 20 | 49 |
| 2023 December | 47 | 21 | 68 |
| 2023 November | 32 | 17 | 49 |
| 2023 October | 41 | 24 | 65 |
| 2023 September | 25 | 19 | 44 |
| 2023 August | 31 | 19 | 50 |
| 2023 July | 34 | 33 | 67 |
| 2023 June | 31 | 27 | 58 |
| 2023 May | 38 | 26 | 64 |
| 2023 April | 20 | 14 | 34 |
| 2023 March | 29 | 24 | 53 |
| 2023 February | 33 | 12 | 45 |
| 2023 January | 29 | 19 | 48 |
| 2022 December | 42 | 30 | 72 |
| 2022 November | 62 | 31 | 93 |
| 2022 October | 39 | 37 | 76 |
| 2022 September | 27 | 34 | 61 |
| 2022 August | 38 | 50 | 88 |
| 2022 July | 37 | 42 | 79 |
| 2022 June | 25 | 37 | 62 |
| 2022 May | 39 | 53 | 92 |
| 2022 April | 29 | 56 | 85 |
| 2022 March | 54 | 39 | 93 |
| 2022 February | 35 | 26 | 61 |
| 2022 January | 37 | 35 | 72 |
| 2021 December | 38 | 41 | 79 |
| 2021 November | 36 | 51 | 87 |
| 2021 October | 45 | 55 | 100 |
| 2021 September | 28 | 37 | 65 |
| 2021 August | 30 | 52 | 82 |
| 2021 July | 25 | 30 | 55 |
| 2021 June | 26 | 45 | 71 |
| 2021 May | 36 | 37 | 73 |
| 2021 April | 80 | 54 | 134 |
| 2021 March | 83 | 43 | 126 |
| 2021 February | 44 | 18 | 62 |
| 2021 January | 33 | 23 | 56 |
| 2020 December | 45 | 32 | 77 |
| 2020 November | 36 | 23 | 59 |
| 2020 October | 30 | 11 | 41 |
| 2020 September | 39 | 20 | 59 |
| 2020 August | 24 | 12 | 36 |
| 2020 July | 26 | 12 | 38 |
| 2020 June | 25 | 17 | 42 |
| 2020 May | 46 | 18 | 64 |
| 2020 April | 37 | 16 | 53 |
| 2020 March | 61 | 17 | 78 |
| 2020 February | 148 | 10 | 158 |
| 2020 January | 82 | 10 | 92 |
| 2019 December | 82 | 24 | 106 |
| 2019 November | 31 | 5 | 36 |
| 2019 October | 21 | 10 | 31 |
| 2019 September | 38 | 13 | 51 |
| 2019 August | 56 | 20 | 76 |
| 2019 July | 41 | 36 | 77 |
| 2019 June | 43 | 32 | 75 |
| 2019 May | 88 | 24 | 112 |
| 2019 April | 59 | 39 | 98 |
| 2019 March | 38 | 24 | 62 |
| 2019 February | 46 | 26 | 72 |
| 2019 January | 30 | 28 | 58 |
| 2018 December | 36 | 40 | 76 |
| 2018 November | 94 | 49 | 143 |
| 2018 October | 143 | 36 | 179 |
| 2018 September | 30 | 23 | 53 |
| 2018 July | 2 | 0 | 2 |
| 2018 June | 2 | 0 | 2 |
| 2018 May | 7 | 0 | 7 |
| 2018 April | 11 | 0 | 11 |
| 2018 March | 15 | 0 | 15 |
| 2018 February | 7 | 0 | 7 |
| 2018 January | 18 | 0 | 18 |
| 2017 December | 9 | 0 | 9 |
| 2017 November | 22 | 0 | 22 |
| 2017 October | 11 | 0 | 11 |
| 2017 September | 13 | 0 | 13 |
| 2017 August | 26 | 0 | 26 |
| 2017 July | 17 | 0 | 17 |
| 2017 June | 19 | 8 | 27 |
| 2017 May | 26 | 7 | 33 |
| 2017 April | 14 | 4 | 18 |
| 2017 March | 9 | 6 | 15 |
| 2017 February | 11 | 3 | 14 |
| 2017 January | 8 | 6 | 14 |
| 2016 December | 16 | 12 | 28 |
| 2016 November | 47 | 6 | 53 |
| 2016 October | 44 | 10 | 54 |
| 2016 September | 36 | 13 | 49 |
| 2016 August | 32 | 2 | 34 |
| 2016 July | 13 | 14 | 27 |
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