Dilemma of belimumab therapy (dis)continuation during pregnancy: Results of a retrospective study in eudravigilance.

INTRODUCTION: The first biologic authorized for systemic lupus erythematosus (SLE) up to this date, belimumab, is currently not recommended for use during pregnancy due to lack of data. Provided that the health of the child begins with the health of the mother, pregnant patients face the dilemma of cessation or continuation of belimumab. If belimumab is stopped, there will be a risk of SLE flare and its consequences for the mother and the foetus. Continuation is also not optimal because of the lack of knowledge on safety for use during pregnancy. AIM: To compare the reported foetal outcomes in SLE patients who stopped scheduled belimumab within the first trimester (group A) and those who continued scheduled belimumab during the first trimester or thereafter (group B). MATERIAL AND METHOD: All belimumab-exposed pregnancy-related reports were extracted from the EudraVigilance (EV) database until March 11th, 2021. After case review, repeated cases, uninformative reports, non-medical elective abortions and foetal chromosomal abnormalities were excluded. Included pregnancies were divided into two groups (group A and B, as described above). Foetal outcomes were divided into live birth or foetal death (due to miscarriage or stillbirth) and were compared between both groups. Furthermore, neonatal outcomes, such as reporting rates of preterm birth, low birth weight and major congenital malformations were compared. RESULTS: No statistical difference in foetal death was observed between group A and B (reported numbers (%) = 32 (46.4) and 11 (52.4), respectively). Odds ratio (OR, [95% Confidence Intervals (CIs)]) of foetal death in group B compared to group A was 1.27 [0.48, 3.32]. Reporting rates of preterm birth and low birth weight were higher - though not statistically different - in group A. CONCLUSION: The positive results of our study are supportive for the continuation of belimumab during pregnancy. Since the analysis is based on spontaneous reports/retrospective data, additional studies are needed to confirm the results.

A case series of bacillus Calmette-Guérin scar reactivation after administration of both mRNA and viral vector COVID-19 vaccines.

AIM: Reactivation of the scar resulting from intradermal injection of bacillus Calmette-Guérin (BCG) is a common specific reaction in Kawasaki's disease. It has also sporadically been associated with viral infections, multisystem inflammatory syndrome in children, influenza vaccination and mRNA COVID-19 vaccination. In this case series, characteristics of BCG scar reactivation after different COVID-19 vaccinations are presented and possible mechanisms are discussed. METHODS: Data were collected from the spontaneous reporting system of the Netherlands Pharmacovigilance Centre Lareb. Descriptives were made for the case reports in which a BCG scar reactivation was detected. RESULTS: Since the start of the COVID-19 vaccination campaign in January 2021, the Netherlands Pharmacovigilance Centre Lareb has received 22 case reports of BCG reactivation after vaccination with a COVID-19 vaccine. In 20 case reports, it concerned mRNA COVID-19 vaccines Moderna (14) and Pfizer (6). In two case reports, the viral vector COVID-19 vaccine AstraZeneca was administered. Erythema and pain were the most frequently reported symptoms and the size of the inflammation was between 1.5 and 5 cm. BCG scar reactivation occurred with a median time to onset of 2 days after the second or booster COVID-19 vaccination, whereas the median time to onset was 7 days after the first COVID-19 vaccination. None of the BCG scar reactivations were treated. CONCLUSIONS: The exact mechanism of the occurrence of BCG scar reactivation remains unknown, but involvement of heat shock protein 65 is suggested. BCG scar reactivation is a nonserious, self-limiting reaction that can occur after vaccination with both mRNA and viral vector COVID-19 vaccines.

Exposure to psychotropic drugs before and during pregnancy: what has changed over the last two decades?

Trends in prescribing psychotropic drugs before and during pregnancy may have changed over the years, but actual information is lacking. We therefore compared and assessed the exposure and acceptance rates of classes of antipsychotic (+ lithium), anxiolytic, sedative/hypnotic, antidepressant, and psychostimulant before and during pregnancy in the past two decades. All singleton pregnancies with ≥1 prescription of psychotropic drug from six months before pregnancy until child's birthdate were identified in the pregnancy subset of the IADB.nl prescription database. The prescription patterns of psychotropics were distinguished as continuation rate (CR), initiation rate (IR), discontinuation rate (DR), total exposure rate (TER), and acceptance rate. Singleton pregnancies exposed to psychotropic drugs before and during pregnancy increased from 118.4 to 136.5 (per 1000 singleton pregnancies) between decades. Changing trends were observed in decade 2, including a high increase in the TER of antipsychotic class (3.3 to 6.8) and antidepressant class (23.0 to 40.6). A marked increase for individual drugs was seen for sertraline (TER: 0.6 to 6.6 and PAT: 35.3% to 82.5%), citalopram (TER: 2.3 to 10.0 and PAT: 51.1% to 74.6%), and quetiapine (TER: 0.4 to 3.1 and PAT: 57.1% to 66.0%). Although the total exposure rates of five classes of psychotropics in singleton pregnancies increased in decade 2, only antidepressant class had a higher acceptance rate during pregnancy. Certain SSRI antidepressants and atypical antipsychotics were more frequently prescribed in decade 2 than in decade 1, reflecting that treatment options were preferred for safer treatment choices.

Switching pattern and dose adjustment of antidepressants before and during pregnancy.

The purpose of the study is to examine the switching pattern and dose adjustment of antidepressants (ADs) prescribed to women from six months before to six months during pregnancy in the Netherlands. The recorded dispenses or refills were collected from the University of Groningen IADB.nl pregnancy subset for all singleton pregnancies in which the mother received ≥ 1 prescription of an AD dispensed before pregnancy and was present in the database at least six months after conception. The rates of continuation, discontinuation, and switching between 2001 and 2020 were assessed for the ADs studied. The mean number of Defined Daily Doses (DDDs) of the most frequently continued ADs used was calculated both before and during pregnancy, and a paired t-test was used to test for significant changes. The continuation rates for AD users, especially for SSRI and SNRI continued users, increased over time from 27% and 19% (2001-2005) to 65% and 65% (2016-2020). The switching rate between ADs remained consistently low from the start of the study (2001-2005) at 2.0% to the end of the study (2016-2020) at 2.3%. Most women who switched between antidepressants during pregnancy received a different SSRI monotherapy (85%), followed by an SNRI (6%), a TCA (4%), and an "other AD" (4%). In most cases observed, the dose adjustment for the mean DDDs during pregnancy compared to the mean DDDs before pregnancy only changed little (less than 10%). Continued use of SSRIs among singleton pregnancies doubled over the study period. The low rate of AD switching and little changes in the DDD adjustment for most AD continuers indicate that pregnant women prefer to continue their prepregnancy medication rather than switch it. Most observed findings cohere with the Dutch national guidelines for antidepressant use during pregnancy.

Body weight gain in clozapine-treated patients: Is norclozapine the culprit?

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options.

Reported congenital malformations after exposure to non-tumour necrosis factor inhibitor biologics: A retrospective comparative study in EudraVigilance.

AIMS: To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitor biologics (non-TNFi biologics) compared to certolizumab pegol (CZP). METHODS: A retrospective comparative study was conducted in the EudraVigilance (EV) database. A safe biologic (CZP) was considered as the reference group. Odds ratios (ORs) for CMs were calculated for each non-TNFi biologic (including abatacept, anakinra, belimumab, ixekizumab, rituximab, secukinumab, tocilizumab, ustekinumab and vedolizumab), versus CZP (quantitative assessment). Then, CM patterns were reviewed in consultation with a clinical geneticist (qualitative assessment). RESULTS: ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Except for vedolizumab, no specific CM patterns were observed for the included non-TNFi biologics. Three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus none in CZP and other investigated non-TNFi biologics). Two of the CCA cases were associated with other neurological CMs (one cerebral ventriculomegaly with microcephaly and one polymicrogyria). This may indicate that these CCAs are related to undiagnosed genetic alterations or are associated with the underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out. CONCLUSION: No special safety signal was identified regarding the occurrence of CMs after exposure to abatacept (n = 64), anakinra (n = 20), belimumab (n = 93), ixekizumab (n = 29), rituximab (n = 57), secukinumab (n = 128), tocilizumab (n = 124) and ustekinumab (n = 215). Regarding observed CCAs in the vedolizumab group (n = 113), no firm conclusions can be made based on available information.

Retroperitoneal fibrosis and ß-blocking agents: Is there an association?

AIMS: Retroperitoneal fibrosis (RPF) is a rare chronic fibro-inflammatory disorder that may be secondary to certain drugs, including ß-blocking agents (BBAs). However, their causative role is unclear. We aimed to investigate this association. METHODS: Disproportionality analysis was carried out on cases from 1985 to 4 October 2020 in VigiBase, the World Health Organization pharmacovigilance database. The Bayesian-based IC025 metric and reporting odds ratio were used in order to assess the adverse event signal. We also analysed all published case reports from the literature regarding BBA-associated RPF to assess the value of suggested supportive clinical evidence. RESULTS: In total, 1599 individual case safety reports of RPF were reported to VigiBase, of which 132 (32%) concerned 16 different single BBA. For 12 of these agents (75%), reporting of RPF was disproportionate, indicating a potential safety signal. Line listing analysis of individual case safety reports showed no consistent time interval from start of BBA to RPF diagnosis (range 0.7-264 mo). Dechallenge was negative or unknown in the majority of cases (74%). In 18 published cases from the literature, time from start of BBA to RPF diagnosis varied widely (range 3-156 mo). BBA were discontinued 6 months before (n = 1) or at the time of RPF diagnosis (n = 17). Most patients (84%) also received RPF specific treatment. Follow-up duration was short (median 5 mo [range 1-24 mo]) and in most cases (83%) relevant follow-up data were lacking. CONCLUSION: Although disproportionality analysis indicated a potential safety signal for RPF associated with BBAs, clinical evidence did not support a cause-and-effect relationship.

Inhibition of CYP2D6 with low dose (5 mg) paroxetine in patients with high 10-hydroxynortriptyline serum levels-A prospective pharmacokinetic study.

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 µg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 µg/L). The shift in number of patients to therapeutic nortriptyline (50-150 µg/L) and safe hydroxynortriptyline (<200 µg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges.

Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers.

Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.

Drug-induced interstitial lung disease: role of pharmacogenetics in predicting cytotoxic mechanisms and risks of side effects.

PURPOSE OF REVIEW: The diagnosis of drug-induced interstitial lung disease (DI-ILD) is challenging and mainly made by exclusion of other possible causes. Toxicity can occur as a cause of drug(s) or drug-drug interactions. In this review, we summarize the possible role of pharmacogenetics of metabolizing enzymes in DI-ILD. RECENT FINDINGS: Knowledge of the genetic predispositions of enzymes involved in drug metabolization and their relation with proposed cytotoxic mechanisms of DI-ILD, in particular direct cell toxicity and free oxygen radical production is increasing. The cytochrome P450 enzyme family and other enzymes play an important role in the metabolism of all sorts of ingested, injected, or inhaled xenobiotic substances. The liver is the major site for metabolism. Metabolic cytotoxic mechanisms have however also been detected in lung tissue. Polymorphisms in genes coding for enzymes that influence metabolic activity may lead to localized (toxic) reactions and tissue damage. This knowledge may be helpful in preventing the risk of DI-ILD. SUMMARY: Drug toxicity can be the consequence of absence or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, it is recommended to reduce the dose or to prescribe an alternative drug, which is metabolized by a different, unaffected enzyme system to prevent toxic side effects. However, enhanced enzyme activity may lead to excessive formation of toxic and sometimes reactive metabolites. Therefore, knowing a patient's drug-metabolizing profile before drug prescription is a promising way to prevent or explain DI-ILD.

Adverse drug event patterns experienced by patients with diabetes: A diary study in primary care.

PURPOSE: Little is known about adverse drug events (ADEs) experienced over time during chronic drug use. The purpose of this study was to assess ADE patterns experienced by patients with diabetes. METHODS: Patients who received an oral glucose-lowering drug completed a daily diary for 13 weeks. The diary asked for experienced symptoms and whether patients related these symptoms to any drug they used. Summaries of Product Characteristics were used to check whether the ADEs were known adverse drug reactions (ADRs) of the drugs used. Patterns of weekly occurring ADEs were assessed with descriptive statistics. RESULTS: We included 78 patients. Almost half of them reported at least one ADE (N = 36; 46%). In total, 80 ADEs were reported. Of these ADEs, 71 (90%) were known ADRs. ADEs lasted less than 1 week in 27 cases (34%) and between 2 and 12 weeks in 15 cases (19%). The remaining ADEs fluctuated (16 cases; 20%) or persisted (22 cases; 28%) during the entire study period. CONCLUSIONS: ADEs experienced by patients with diabetes can fluctuate or persist over long periods of drug use.

Time to onset in statistical signal detection revisited: A follow-up study in long-term onset adverse drug reactions.

PURPOSE: In a previous study, we developed a signal detection method using the time to onset (TTO) of adverse drug reactions (ADRs). The aim of the current study was to investigate this method in a subset of ADRs with a longer TTO and to compare its performance with disproportionality analysis. METHODS: Using The Netherlands's spontaneous reporting database, TTO distributions for drug-ADR associations with a median TTO of 7 days or more were compared with other drugs with the same ADR using the two-sample Anderson-Darling (AD) test. Presence in the Summary of Product Characteristics (SPC) was used as the gold standard for identification of a true ADR. Twelve combinations with different values for the number of reports and median TTO were tested. Performance in terms of sensitivity and positive predictive value (PPV) was compared with disproportionality analysis. A sensitivity analysis was performed to compare the results with those from the previous study. RESULTS: A total of 38 017 case reports, containing 32 478 unique drug-ADR associations. Sensitivity was lower for the TTO method (range 0.08-0.34) compared with disproportionality analysis (range 0.60-0.87), whereas PPV was similar for both methods (range 0.93-1.0). The results from the sensitivity analysis were similar to the original analysis. CONCLUSIONS: Because of its low sensitivity, the developed TTO method cannot replace disproportionality analysis as a signal detection tool. It may be useful in combination with other methods.

Using Web-Based Questionnaires to Assess Medication Use During Pregnancy: A Validation Study in 2 Prospectively Enrolled Cohorts.

Medication use is often underreported in paper-based questionnaires or interviews. Web-based questionnaires may improve recall of medication use, but data on their validity are currently lacking. Participants in the Pregnancy and Infant Development (PRIDE) Study (2014-2016; n = 557) and the Pregnancy Drug Registry (pREGnant) (2015-2016; n = 169) completed a 6-week paper-based medication diary during gestational weeks 19-24 or 26-31. In week 34, they completed a Web-based questionnaire with questions on medication names, time period and frequency of use, and quantity taken. To assess the degree of underreporting, we calculated the questionnaire's sensitivity using the medication diary as the reference standard. Sensitivity was high for many medication groups, including antiepileptic medication (sensitivity (Sn) = 0.96, 95% confidence interval (CI): 0.89, 1.00), antacids (Sn = 0.89, 95% CI: 0.86, 0.93), and iron preparations (Sn = 0.81, 95% CI: 0.64, 0.98). However, medications for short-term use were underreported more frequently, with sensitivities of 0.54 (95% CI: 0.35, 0.72) for antihistamines, 0.63 (95% CI: 0.57, 0.69) for analgesic and antipyretic agents, and 0.57 (95% CI: 0.51, 0.64) for acetaminophen. Shortening the period of time between exposure and questionnaire administration increased sensitivity substantially. In conclusion, underreporting in Web-based questionnaires is limited for many medication groups. In prospective studies, underreporting of medications for short-term use may be reduced by decreasing the interval between consecutive questionnaires.

A prediction model-based algorithm for computer-assisted database screening of adverse drug reactions in the Netherlands.

PURPOSE: The statistical screening of pharmacovigilance databases containing spontaneously reported adverse drug reactions (ADRs) is mainly based on disproportionality analysis. The aim of this study was to improve the efficiency of full database screening using a prediction model-based approach. METHODS: A logistic regression-based prediction model containing 5 candidate predictors was developed and internally validated using the Summary of Product Characteristics as the gold standard for the outcome. All drug-ADR associations, with the exception of those related to vaccines, with a minimum of 3 reports formed the training data for the model. Performance was based on the area under the receiver operating characteristic curve (AUC). Results were compared with the current method of database screening based on the number of previously analyzed associations. RESULTS: A total of 25 026 unique drug-ADR associations formed the training data for the model. The final model contained all 5 candidate predictors (number of reports, disproportionality, reports from healthcare professionals, reports from marketing authorization holders, Naranjo score). The AUC for the full model was 0.740 (95% CI; 0.734-0.747). The internal validity was good based on the calibration curve and bootstrapping analysis (AUC after bootstrapping = 0.739). Compared with the old method, the AUC increased from 0.649 to 0.740, and the proportion of potential signals increased by approximately 50% (from 12.3% to 19.4%). CONCLUSIONS: A prediction model-based approach can be a useful tool to create priority-based listings for signal detection in databases consisting of spontaneous ADRs.

The value of time-to-onset in statistical signal detection of adverse drug reactions: a comparison with disproportionality analysis in spontaneous reports from the Netherlands.

PURPOSE: In pharmacovigilance, the commonly used disproportionality analysis (DPA) in statistical signal detection is known to have its limitations. The aim of this study was to investigate the value of the time to onset (TTO) of ADRs in addition to DPA. METHODS: We performed a pilot study using individual case safety reports (ICSRs) for three drugs (Cervarix®, nitrofurantoin and simvastatin) from the Lareb spontaneous reporting database. TTO distributions for drug - ADR associations were compared to other ADRs for the same drug and to other drugs for the same ADR using two-sample Anderson-Darling testing. Statistically significant associations were considered true positive (TP) signals if the association was present in the official product information of the drug. Sensitivity and specificity for the TTO method were compared with the DPA method. As a measure of disproportionality, the reporting odds ratio (ROR) was used. RESULTS: In general, sensitivity was lower, and specificity was higher for the TTO method compared to DPA. The TTO method showed similar sensitivity for all three drugs, whereas specificity was lower for Cervarix®. Eight additional TP signals were found using the TTO method compared to DPA. CONCLUSIONS: Our study shows that statistical signal detection based on the TTO alone resulted in a limited number of additional signals compared to DPA. We therefore conclude that the TTO method is of limited value for full database statistical screening in our setting. Copyright © 2016 John Wiley & Sons, Ltd.

Validation of a Novel Method to Assess the Clinical Quality of Information in Pregnancy-Related Pharmacovigilance Case Reports: A ConcePTION Project.

BACKGROUND: To assess the causal relationship between a medicinal product and a reported event, relevant information needs to be present. Information elements for assessing cases of exposure to medicinal products during pregnancy were predefined and used in a new tool to assess the quality of information. However, the extent in which the presence or absence of these predefined information elements is associated with the overall clinical quality of these cases, as evaluated by pharmacovigilance experts, remains uncertain. OBJECTIVE: We aimed to validate a novel method to assess the clinical quality of information in real-world pregnancy pharmacovigilance case reports. METHODS: The clinical quality of case reports regarding medicinal product exposure and pregnancy-related outcomes was appraised from spontaneous reports, literature, Teratology Information Services (UK and Switzerland), The Dutch Pregnancy Drug Register, the Gilenya pregnancy registry and the Enhanced PV programme of Novartis. Assessment was done by means of the novel standardised tool based on the presence and relevance of information, and by expert judgement. The novel tool was validated compared to the expert assessment as the gold standard expressed as the area under the receiver operating characteristic curves, after which the sensitivity and specificity were calculated using cross-tabulations. Inter-rater variability was determined by means of weighted Cohen's kappa. RESULTS: One hundred and eighty-six case reports were included. The clinical quality score as assessed by the novel method was divided into three categories with cut-off values of 45% (poor to intermediate) and 65% (intermediate to excellent). Sensitivity was 0.93 and 0.96 for poor to intermediate and intermediate to excellent, respectively. Specificity was respectively 0.52 and 0.73. Inter-rater variability was 0.65 (95% confidence interval 0.53-0.78) for the newly developed approach, and 0.40 (95% confidence interval 0.28-0.52) for the gold standard assessment. CONCLUSIONS: The tool described in this study using the presence and relevance of elements of information is the first designed, validated and standardised method for the assessment of the quality of information of case reports in pregnancy pharmacovigilance data. This method confers less inter-rater variability compared with a quality assessment by experts of pregnancy-related pharmacovigilance data.

Improving Data Collection in Pregnancy Safety Studies: Towards Standardisation of Data Elements in Pregnancy Reports from Public and Private Partners, A Contribution from the ConcePTION Project.

INTRODUCTION AND OBJECTIVE: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. METHODS: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. RESULTS: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). CONCLUSIONS: Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.

The Dutch Pregnancy Drug Register: Suitable to Study Paternal Drug Exposures?

Paternal medication use around the time of conception is common, but information about its effects on pregnancy outcome and the health of the child is generally limited. The aim of this study is to examine the feasibility of studying paternal exposure in the Dutch Pregnancy Drug Register by using immunosuppressants as a proof of concept. In 113 of 15,959 pregnancies, long-term paternal immunosuppressant use was reported 3 months before conception. In total, 134 immunosuppressants were used. Pregnancy outcome was known for 54 cases and was in accordance with previous findings. Two spontaneous abortions, two premature births, six small for gestational age babies, and two major congenital malformations were reported. Time to pregnancy (TTP) was known for 9548 pregnancies, including 89 with paternal immunosuppressant use. TTP analysis did not show a difference in pregnancies with paternal immunosuppressant use compared to the control group. Moreover, the number of fertility treatments in the paternal immunosuppressant group was similar to the control group. In our opinion, it is feasible to use the Dutch Pregnancy Drug Register to study the effects of paternal exposure on pregnancy outcome. However, to study the potential effects on fertility, more information is needed, particularly since the beginning of pregnancy attempts.