The risk of miscarriage after COVID-19 vaccination before and during pregnancy.

PURPOSE: Pregnant women are at higher risk of severe illness and adverse pregnancy outcomes due to a SARS-CoV-2 infection, which can be prevented by vaccination. Observational studies are needed to ascertain the safety of COVID-19 vaccination during pregnancy. We aimed to determine whether COVID-19 vaccination before and during pregnancy is associated with the risk of miscarriage. METHODS: In this cohort study, we included 4640 pregnant women (mean age: 32.8 ± 3.7 years) from the Dutch Pregnancy Drug Register between February 2021 and August 2022. Information on COVID-19 vaccinations, miscarriage, and confounders was self-reported, using web-based questionnaires. The hazard ratio (HR) of miscarriage (in gestational weeks 6-20) after a COVID-19 vaccination, was estimated using the survival analyses. A COVID-19 vaccination during pregnancy (≥1 COVID-19 vaccination between week 2 and 20 of pregnancy) was included as a time-dependent exposure and vaccination prior to pregnancy was included as a binary exposure. RESULTS: A total of 3202 pregnant women (69%) received ≥1 COVID-19 vaccine in gestational week 2-20. We observed no association of vaccination during pregnancy with the risk of miscarriage (adjusted HR = 1.29, 95% CI = 0.93-1.74). Vaccination prior to pregnancy, however, was associated with a decreased risk of miscarriage (adjusted HR = 0.69, 95% CI = 0.48-0.99). CONCLUSIONS: We demonstrated that COVID-19 vaccination during pregnancy is not associated with an increased risk of miscarriage in gestational weeks 6-20. This study adds to the growing body of evidence demonstrating the safety of COVID-19 vaccination during pregnancy.

Maternal first trimester COVID-19 vaccination and risk of major non-genetic congenital anomalies.

BACKGROUND: Information regarding the risk of early pregnancy COVID-19 vaccination on the development of major congenital anomalies in the offspring is still limited. Here, we study the association between any COVID-19 vaccination during the 1st trimester and at least one major non-genetic congenital anomaly in the offspring. METHODS: We used data from the Dutch Pregnancy Drug Register, an ongoing cohort study. We selected participants with a pregnancy that ended after at least 20 weeks gestation. Pregnant participants self-reported their COVID-19 vaccination status and the presence of congenital anomalies in the offspring. We used logistic regression analyses to study the association between 1st trimester COVID-19 vaccination (gestational week 2 + 0 to 12 + 6) and the risk of at least one major non-genetic congenital anomaly in the offspring. Clustering of anomalies on the ICD10 level by 1st trimester COVID-19 vaccination status was explored using Fisher exact tests. RESULTS: We included 3721 participants of whom 795 (21.4%) were COVID-19 vaccinated during the 1st trimester. The percentage of participants who gave birth to a child with at least one major non-genetic congenital anomaly was comparable between participants who were 1st trimester vaccinated (1.1%) and participants who were not (1.2%) (adjusted odd ratio 0.78 [95% confidence interval 0.35-1.71]). We found no clustering of major non-genetic congenital anomalies by 1st trimester COVID-19 vaccination status (p > .05). CONCLUSIONS: There were no indications of an increased risk of major non-genetic congenital anomalies in the offspring after maternal 1st trimester COVID-19 vaccination. Our findings suggest COVID-19 vaccines are safe during early pregnancy.

Menstrual abnormalities after COVID-19 vaccination in the Netherlands: A description of spontaneous and longitudinal patient-reported data.

AIMS: During the COVID-19 vaccination campaigns, the number of reports of menstrual abnormalities increased rapidly. Here, we describe the nature and potential risk factors associated with menstrual abnormalities based on spontaneously reporting data as well as data from a prospective cohort event monitoring (CEM) study as these are poorly studied. METHODS: Reports of menstrual abnormalities received by the Netherlands Pharmacovigilance Centre Lareb in the spontaneous reporting system between February 2021 and April 2022 were summarized. In addition, logistic regression analysis was performed on the reported menstrual abnormalities in the CEM study to assess the association between person characteristics, prior SARS-CoV-2 infection and use of hormonal contraceptives and the occurrence of menstrual abnormalities after vaccination. RESULTS: We analysed over 24 000 spontaneous reports of menstrual abnormalities and over 500 episodes (among 16 929 included women) of menstrual abnormalities in the CEM study. The CEM study showed an incidence of 41.4 per 1000 women aged ≤54 years. Amenorrhoea/oligomenorrhoea and heavy menstrual bleeding collectively accounted for about half of all abnormalities reported. Significant associations were observed for the age group 25-34 years (odds ratio 2.18; 95% confidence interval 1.45-3.41) and the Pfizer vaccine (odds ratio 3.04; 95% confidence interval 2.36-3.93). No association was observed for body mass index and presence of most comorbidities assessed. CONCLUSION: The cohort study showed a high incidence of menstrual disorders among women aged ≤54 years, and this observation was supported by the analysis of spontaneous reports. This suggests that a relation between COVID-19 vaccination and menstrual abnormalities is plausible and should be further investigated.

Sex-disaggregated outcomes of adverse events after COVID-19 vaccination: A Dutch cohort study and review of the literature.

Background: Albeit the need for sex-disaggregated results of adverse events after immunization (AEFIs) is gaining attention since the COVID-19 pandemic, studies with emphasis on sexual dimorphism in response to COVID-19 vaccination are relatively scarce. This prospective cohort study aimed to assess differences in the incidence and course of reported AEFIs after COVID-19 vaccination between males and females in the Netherlands and provides a summary of sex-disaggregated outcomes in published literature. Methods: Patient reported outcomes of AEFIs over a six month period following the first vaccination with BioNTech-Pfizer, AstraZeneca, Moderna or the Johnson&Johnson vaccine were collected in a Cohort Event Monitoring study. Logistic regression was used to assess differences in incidence of 'any AEFI', local reactions and the top ten most reported AEFIs between the sexes. Effects of age, vaccine brand, comorbidities, prior COVID-19 infection and the use of antipyretic drugs were analyzed as well. Also, time-to-onset, time-to-recovery and perceived burden of AEFIs was compared between the sexes. Third, a literature review was done to retrieve sex-disaggregated outcomes of COVID-19 vaccination. Results: The cohort included 27,540 vaccinees (38.5% males). Females showed around two-fold higher odds of having any AEFI as compared to males with most pronounced differences after the first dose and for nausea and injection site inflammation. Age was inversely associated with AEFI incidence, whereas a prior COVID-19 infection, the use of antipyretic drugs and several comorbidities were positively associated. The perceived burden of AEFIs and time-to-recovery were slightly higher in females. Discussion: The results of this large cohort study correspond to existing evidence and contribute to the knowledge gain necessary to disentangle the magnitude of the effect sex in response to vaccination. Whilst females have a significant higher probability of experiencing an AEFI than males, we observed that the course and burden is only to a minor extent different between the sexes.

Optimizing Safety Surveillance for COVID-19 Vaccines at the National Pharmacovigilance Centre Lareb: One Year of COVID-19 Vaccine Experience.

INTRODUCTION: Due to the COVID-19 vaccination campaign, national pharmacovigilance (PV) centres had to deal with high volumes of Individual Case Safety Reports (ICSRs) that needed to be processed and assessed in a short time span. This necessitated the development of a dedicated system to enable near real-time vaccine safety monitoring at the Dutch PV Centre Lareb. OBJECTIVES: To describe infrastructure, processes and Adverse Events Following Immunisation (AEFIs) reported for vaccine safety monitoring of COVID-19 vaccines during a large-scale vaccination campaign in the Netherlands. METHODS: A COVID-19 tailored vaccine web-based reporting form collected information on the vaccine administered, AEFIs and other (medical) information. A fully automated process for ICSRs enabled the handling of the majority of common and known reported AEFIs. All other ICSRs were triaged daily and processed separately. There were daily signal detection meetings and weekly reports for batch analysis. RESULTS: In 2021, Lareb received 184,411 ICSRs, a reporting rate of 0.67% for vaccines given in the Netherlands. 887,954 AEFIs were reported, mostly well-known, nonserious AEFIs; 2.4% were serious and 0.3% were fatal. 33.1% of all ICSRs were processed fully automatically. Based on the daily triage, 4.2% were flagged as 'high priority'; 62.7% as 'low-priority'. Twenty-seven signals and news stories about the COVID-19 vaccines were disseminated. CONCLUSIONS: Due to automatic processing of well-known AEFIs, daily triage and signal detection meetings, 99.9% of the ICSRs were processed within the compliance timeframe to Eudravigilance, and signal detection was performed during a large-scale vaccination campaign. These experiences may serve as a blueprint for future mass vaccination programs.

Description of Frequencies of Reported Adverse Events Following Immunization Among Four Different COVID-19 Vaccine Brands.

INTRODUCTION: The rapid rollout of coronavirus disease 2019 (COVID-19) vaccines for a large proportion of the population necessitates a strong emphasis on safety. Complementary to the existing spontaneous reporting system, The Netherlands Pharmacovigilance Centre Lareb conducted patient-reported cohort event monitoring (CEM). OBJECTIVE: The primary aim was to investigate differences in the frequencies of any and commonly reported, 'well-known', systemic adverse events following immunization (AEFIs) with four COVID-19 vaccines (Pfizer's Comirnaty®, Moderna's Spikevax®, AstraZeneca's Vaxzevria® and the Janssen vaccine). As a secondary aim, we analyzed the frequencies of well-known systemic adverse events after the first and, if applicable, second COVID-19 vaccinations, taking into account age, sex and prior COVID-19 infection. METHODS: Patient-reported outcomes (PROs) in the Netherlands starting in February 2021 were analyzed using a prospective cohort design. RESULTS: Data of 27,554 participants who received one vaccination and 20,682 participants who received complete immunization were analyzed. The percentage of patients reporting any AEFI was high and ranged from approximately 53% for the Pfizer vaccine to approximately 94% for the Moderna vaccine. The frequency of serious AEFIs was low, with the highest frequency found for the AstraZeneca vaccine (0.228%). AEFIs were most often experienced by participants receiving the first dose of the AstraZeneca and Janssen vaccines and the second dose of the Moderna vaccine; the Pfizer vaccine was associated with the lowest rate of AEFIs. Participants with a COVID-19 history before vaccination experienced commonly reported systemic AEFIs more frequently after the first vaccination than after the second vaccination. Women and young people experienced more AEFIs than men and older people, respectively. CONCLUSIONS: The analysis of a large cohort provides important information about the rates of AEFIs across age groups, among brands of vaccines and between those with and without prior COVID-19 infection. Participants reported a high number of AEFIs in general, but the frequency of serious AEFIs was low.

COVID-19 vaccine reactogenicity - A cohort event monitoring study in the Netherlands using patient reported outcomes.

OBJECTIVES: To explore factors that are associated with reactogenicity in general and systemic after the first dose of COVID-19 vaccine in the Netherlands. DESIGN: A web-based prospective cohort design using patient reported outcomes (PROs). SETTING: Any person who has been vaccinated with any brand of COVID-19 vaccine in the Dutch COVID immunization programme. PARTICIPANTS: 22,184 participants. Of these, 13,959 (62.9%) experienced reactogenicity in general and 11,979 (54.0%) systemic reactogenicity within 7 days after vaccination. MAIN OUTCOME MEASURES: Factors that are associated with the occurrence of reactogenicity after COVID-19 vaccination. RESULTS: Compared to the Comirnaty® vaccine, the highest odds ratio (OR) for developing reactogenicity was for the Vaxzevria® vaccine (OR 5.18) followed by Spikevax® (OR 2.16), and Janssen (OR 1.65). Participants with a history of COVID-19 disease had a 3.10 increased odds for reactogenicity. Women had a 2.08 increased odds compared to men. Older participants experienced less reactogenicity. Compared to the age group < 50, the ORs for the age groups 50-60, 61-79, and ≥80 were 0.36, 0.15, and 0.10 respectively. The use of an antipyretic drug, or a drug for nervous system disorders gave an increased odds of 1.34 and 1.16 respectively. A body mass index of 25.0-29.9 and over 30 was negatively associated with reactogenicity (OR 0.87 and OR 0.72 respectively). Comorbidities that were associated with reactogenicity were cardiac disorders (OR 1.26), respiratory disorders (OR 1.31), psychiatric disorders (1.37), reproductive disorders (OR 1.54), and eye disorders (OR 1.55). The factors associated with systemic reactogenicity were mostly comparable, but there were differences for comorbidities, drug use, and the strength of the regression coefficient. CONCLUSIONS: This extensive study with over 22,000 vaccine recipients in the Netherlands demonstrated that, taken into account all factors in the model, the Comirnaty® vaccine gave the least and the Vaxzevria® vaccine the most reactogenicity in general and systemic after the first dose. Also a person with a history of COVID-19 disease, female sex and younger age had an increased odds for experiencing reactogenicity after vaccination.

Numbers of spontaneous reports: How to use and interpret?

Due to the high intensity of the COVID-19 vaccination campaigns and heightened attention for safety issues, the number of spontaneous reports has surged. In the Netherlands, pharmacovigilance centre Lareb has received more than 100 000 reports on adverse events following immunization (AEFI) associated with Covid-19 vaccination. It is tempting to interpret absolute numbers of reports of AEFIs in signal detection. Signal detection of spontaneously reported adverse drug reactions has its origin in case-by-case analysis, where all case reports are assessed by clinically qualified assessors. The concept of clinical review of cases-even if only a few per country-followed by sharing concerns of suspicions of potential adverse reactions again proved the strength of the system. Disproportionality analysis can be useful in signal identification, and comparing reported cases with expected based on background incidence can be useful to support signal detection. However, they cannot be used without an in-depth analysis of the underlying clinical data and pharmacological mechanism. This in-depth analysis has been performed, and is ongoing, for the signal of vaccine-induced immune thrombotic thrombocytopenia (VITT) in relation to the AstraZeneca and Janssen Covid-19 vaccines. Although not frequency or incidence rates, reporting rates can provide an impression of the occurrence of the event. But the unknown underreporting should also be part of this context. To quantify the incidence rates, follow-up epidemiological studies are needed.

[Self-reported maternal adverse events of covid-19 vaccination during pregnancy]. / Maternale bijwerkingen na covid-19-vaccinatie in de zwangerschap.

OBJECTIVE: To describe the self-reported maternal adverse events (AEs) of covid-19 vaccination during pregnancy. DESIGN: The Dutch Pregnancy Drug Register ("Moeders van Morgen"), is a prospective cohort study among pregnant women in the Netherlands. METHOD: Using online questionnaires, women reported whether they received a covid-19 vaccination and the self-perceived AEs after vaccination. We included women who received their first covid-19 vaccination during pregnancy. We assessed the maternal AEs by vaccine dose, type of vaccine (BioNTech/Pfizer, Moderna, AstraZeneca, and Janssen) and moment of vaccination in pregnancy. RESULTS: 4348 women received their first covid-19 vaccination during pregnancy and were included. Of these, 2787 women also reported a second dose during pregnancy. After the first dose, AEs were less often reported for BioNTech/Pfizer (56% ≥1 AE), compared to Moderna (68% ≥1 AE) or AstraZeneca (87% ≥1 AE). After the second dose, AEs were less often reported for BioNTech/Pfizer (44% ≥1 AE) compared to Moderna (76% ≥1 AE). Injection site reactions, myalgia and fatigue were reported most frequently. There was large variation in the percentage reporting pyrexia/fever between the different vaccines (3%, 22%, and 10% after the second dose of BioNTech/Pfizer, Moderna, and Astrazeneca respectively). There were no major differences in the rates of AEs between vaccination in the first, second, or third trimester. CONCLUSION: The adverse event profile among women who were vaccinated against covid-19 during pregnancy do not indicate any safety concerns. Considering the reported maternal AEs, the BioNTech/Pfizer vaccine seems best for vaccination during pregnancy.

Assessing the Impact on Health of Pharmacovigilance Activities: Example of Four Safety Signals.

INTRODUCTION: The impact of pharmacovigilance activities on public health remains under-investigated, and measuring the impact on health of pharmacovigilance activities for a specific safety signal is challenging. OBJECTIVE: To gain more insight into the methodological challenges and the data required, we assessed the impact of pharmacovigilance on public health for four identified product-specific safety signals using publicly available data in the Netherlands. The assessment was on the impact of the intertwined and complementary steps of the pharmacovigilance pathways. METHODS: The impact of pharmacovigilance on public health was assessed using the assessment support tool and 'open data' from the Netherlands for four different types of pharmacovigilance safety signals: (1) off-label use of cyproterone acetate/ethinyloestradiol (CPA/EE) and thrombotic risk after pharmacovigilance measures after 2014; (2) pergolide and the risk of cardiac valvulopathy after pharmacovigilance activities in 2003; (3) proton pump inhibitors and the risk of hypomagnesaemia after pharmacovigilance activities in 2011; (4) rosiglitazone withdrawal from the market because of cardiovascular effects in 2010. RESULTS: For the signals on CPA/EE and pergolide, a crude estimation of the impact could be made with varying degrees of assumptions based on the risk described in the literature and utilisation data. CONCLUSION: This article highlights the methodological challenges and the data required to assess the impact of product-specific safety signals. A structured assessment support tool can be used as a guide for the necessary data elements and steps needed for the measurement or estimation of impact of pharmacovigilance activities on public health, provided that the appropriate data are available.

Collaboration between patient and pharmacovigilance organizations to gain insight into adults' experiences with drug use and ADRs for the treatment of ADHD.

BACKGROUND: Patient organizations have good access to patients, which can be of interest in gaining knowledge about patients' experiences with drugs. The aim of this study is to investigate if a collaboration between a pharmacovigilance center and an ADHD patient organization can give more insight in patients' experiences with drug use and ADRs for the treatment of AD(H)D. METHODS: Pharmacovigilance Centre Lareb and ADHD patient organization Impuls & Woortblind created a web-based questionnaire asking about patients' experiences with drug use and ADRs. Patients were approached to participate by e-mail and an open web-link. They were also asked to report ADRs through the official reporting form of Lareb. RESULTS: A total of 1160 patients completed the questionnaire, of which 75.2% of the respondents experienced ADRs and 60.7% discontinued treatment because of an ADR. More than 70% experienced positive effects of their drugs. Additionally, 5.0% of the respondents reported their ADRs to Lareb. CONCLUSIONS: Collaboration with patient organizations provide useful insight into patients' experiences with drug use and ADRs taking into account establishing clear 'rules of engagement'. An active approach to collaborate with patient organizations is a way forward to gain more information about drug use and ADRs in a selective cohort.

Aim and Design of pREGnant, the Dutch Pregnancy Drug Register.

Information on the safety of medication use during pregnancy and breastfeeding is scarce, yet use of medication among pregnant and breastfeeding women is widespread. The pREGnant, the Dutch Pregnancy Drug Register, was set up to obtain insight into medication use among pregnant and breastfeeding women and potential effects on maternal and fetal/infant health. The systematically documented, good quality data on medication use during pregnancy and lactation in pREGnant will be used in signal detection, epidemiologic studies and counseling of healthcare providers and patients. The register has a prospective cohort design. The population is derived from pregnant women throughout the Netherlands. Data collection started in April 2014 and enrollment of women is continuous and is characterized by a relative high proportion of women born in the Netherlands with a high education compared with the general Dutch pregnant population. Data on current pregnancy, obstetric history, maternal lifestyle, health and medication use, delivery, and infant health are collected through web-based questionnaires completed by the participating women (three times during pregnancy and three times during the infant's first year of life). If permission is given, the self-reported data can be complemented with information retrieved from Perined, the perinatal registry of the Netherlands, and from obstetric and medical records, and/or pharmacy records. Here, we provide detailed information on the design of the pREGnant, the Dutch Pregnancy Drug Register, as well as descriptive information on characteristics of the participants so far. Currently, steps are being taken to implement the register on a large scale in the Netherlands.

Surveillance of Drug Safety During Pregnancy: Insight in Current International Activities, Future Intentions and Need for Support of National Pharmacovigilance Centres.

INTRODUCTION: Surveillance of drug safety during pregnancy is a special interest of pharmacovigilance (PV). The role that national PV centres take in this field is, however, unclear. AIM: The aim of this study was to provide insight into current activities, future intentions and need for support of national PV centres in the field of drug safety during pregnancy. METHOD: A web-based questionnaire was used to ask PV centres about their current activities concerning the surveillance of drug safety during pregnancy, their intentions to implement or improve activities and need for support. For these three main topics, questions were posed about spontaneous adverse drug reaction (ADR) reporting, additional activities to obtain information, signal detection and informing healthcare professionals and the public. RESULTS: The questionnaire was sent to PV centres of 172 countries. Response was 40%. In general, the PV centres received limited numbers of reports of ADRs in the (unborn) child, related to drug exposure during pregnancy. Signal detection in pregnancy cases is carried out by 8 out of 58 PV centres (13.5%). Most PV centres mention they have intentions to implement or improve activities, mainly for spontaneous reporting (69.4%) and methods for signal detection (67.2%). Support was needed for all topics of the questionnaire. CONCLUSION: Current activities of national PV centres concerning drug safety during pregnancy are limited. The majority of PV centres are, however, willing to improve or implement activities. Programmes should be set up in order to support and stimulate PV centres with these activities. The aim of all these activities is to increase knowledge about the safety of drugs during pregnancy.

Cytochrome P450 genotype and aggressive behavior on selective serotonin reuptake inhibitors.

Letter in reply to: Eikelenboom-Schieveld SJM, Fogleman JC. Letter to the Editor. Pharmcogenomics 19(14), 1095-1096 (2018) [ 1 ]. Regarding: Ekhart, Matic M, Kant A, van Puijenbroek E, van Schaik R. CYP450 genotype and aggressive behavior on selective serotonin reuptake inhibitors. Phamacogenomics 18(7), 613-620 (2017) [ 2 ].