The present study aims to contribute to the available experience on the systemic use of five different anthelmintics during pregnancy (albendazole, mebendazole, praziquantel, pyrantel and pyrvinium). Particular focus was placed on the occurrence of major birth defects and pregnancy loss following first-trimester exposure. As the assessed agents differ considerably in terms of their chemical structure and mechanism of action, they were analyzed separately. A total of 282 pregnancies with exposure to the study medication were recorded in the Embryotox database (January 1, 2000-February 28, 2023) and analyzed descriptively. Among 75 live-born infants with first-trimester exposure to mebendazole, five major malformations were reported, three of which were heart defects. Of the 21 live-born infants exposed to pyrantel in the first trimester, two were affected by aplasia cutis congenita of the scalp, one of whom was co-exposed to thiamazole. Among 47 live-born children with first-trimester pyrvinium exposure, one major birth defect was reported. No major malformations were observed among 4 and 10 live-born children exposed to praziquantel and albendazole, respectively. Given the limitations, the findings should be interpreted as descriptive observations and possible signals only. Further investigations with larger cohorts are required.

Background:Since 2008, the open-access internet portal "Embryotox" has provided evidence-based information on drug safety during pregnancy and breastfeeding. The German website, designed for health care professionals, comprises fact sheets about 400 drugs and is maintained by the Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy at the Charité - Universitätsmedizin Berlin. In 2024, it was accessed more than 5 million times. Objective:This study aimed to evaluate who is using the website, how it is being used, and to what extent it meets users' needs. Methods:Data were collected between 2022 and 2023 through a sequential mixed methods design incorporating explanatory and exploratory elements. Online questionnaire 1 contained questions on user characteristics, clinical specifics of use, comprehensibility, and changes in risk assessment or drug therapy following fact sheet use. Qualitative data were generated through semistructured phone interviews, with interviewees sampled from the main user groups identified in questionnaire 1 (patients, physicians, pharmacists, and midwives). Kuckartz's content analysis was used to analyze data on users' trust and the functions of website use for different stakeholder groups. Online questionnaire 2 collected data from the main user groups on their decision-making based on Embryotox fact sheets. This questionnaire was developed based on the findings from semistructured interviews on the functions of website use. Answers in both questionnaires included multiple-choice options or ratings on a Likert scale from 0 (not at all) to 10 (fully); data were analyzed using descriptive statistics. Results:Questionnaire 1 was completed by 14,562 users, including 10,860 patients, 1676 physicians, 550 pharmacists, and 364 midwives. Of the physicians, 27.2% (456/1676) were obstetricians and gynecologists, and 22.7% (381/1676) were general practitioners. For physicians, the mean of comprehensibility ratings was 9.39 (pharmacists 9.25; midwives 9.14), and for patients 8.80. Following fact sheet use, 66.6% (9694/14,562) of all users changed their risk perception, and 22.3% (2252/10,083) of users in a specific treatment setting considered changing drug treatment. Qualitative content analysis revealed that users highly trusted the information in the fact sheets for a number of reasons, including recommendations from other users, the scientific basis of the website, and the authority of the Embryotox Center as a university-based specialist department for drug safety in pregnancy and lactation. Functions of fact sheet use differed depending on the stakeholder group. A total of 793 users, mostly physicians and patients, fully completed questionnaire 2, specifying typical clinical situations and benefits of fact sheet use for shared decision-making. Benefits included facilitating the decision-making process and increasing confidence in it. Conclusions:The information provided in the Embryotox fact sheets was generally perceived as both comprehensible and trustworthy, supporting and facilitating the decision-making process. Embryotox is used successfully by health care providers and patients in routine health care settings, helping to improve drug safety for pregnant and breastfeeding women.

OBJECTIVES:This observational cohort study evaluates the risk of major birth defects after maternal mRNA COVID-19 vaccination in the first trimester of pregnancy. METHODS:Outcomes of prospectively ascertained pregnancies with at least one mRNA COVID-19 vaccination in the first trimester (gestational week 2 + 0 to 12 + 6) were compared with a cohort of unvaccinated pregnant women of the same period, whose data were collected using the same approach. The enrolment of study cases was conducted over a period of 21 months. For inclusion in the study, a structured pregnancy follow-up had to be completed afterwards. The reported congenital anomalies were classified according to EUROCAT. Relevant maternal characteristics were considered and adjusted ORs were calculated using logistic regression. RESULTS:The exposed study cohort included 1828 pregnant women who were vaccinated with an mRNA vaccine in the first trimester. The unexposed comparison cohort consisted of 1955 pregnant women. Sixty-eight major congenital malformations have been observed in the vaccinated and 53 in the unexposed cohort (3.86% vs. 3.09%). The analysis resulted in an adjusted OR of 1.30 (95% CI: 0.90-1.86). A wide range of performed sensitivity analyses was in line with this finding. CONCLUSIONS:We did not detect a statistically significant increase in the overall birth defect rate after maternal mRNA COVID-19 vaccination in the first trimester.

Standardised procedures for performing and reporting safety monitoring studies investigating medications use in pregnancy may help improve data quality and the speed of data generation. The objective of this study was to provide recommendations on the statistical analysis and reporting of single-arm pregnancy medication safety studies using primary source datasets. A Delphi consensus-setting protocol was used to acquire agreement on recommendations from experts with extensive knowledge and experience in conducting studies investigating medication safety in pregnancy. A series of recommendations, along with their scientific justifications and examples of how to calculate and describe exposure and outcome incidences, were critiqued and improved through a series of online Delphi review rounds. Agreement to inclusion scoring was assessed using a five-point Likert scale. Recommendations with a median Likert-scale score of at least 4, where ≥ 80

Background Embryotox.de offers evidence-based information on drug safety during pregnancy and lactation free of charge and independent from pharmaceutical industry. There are more than five million users per year. Utilization of embryotox.de in routine healthcare was investigated in a mixed-methods study funded by the G-BA Innovation Fund. The following sub-analysis focuses on the use by pharmacists. Methods User feedback was obtained by two different online questionnaires (multiple choice options or ratings on a Likert Scale ranging from 0 "not at all" to 10 "completely"). Questionnaire 1 included questions on user characteristics, clinical circumstances, comprehensibility and consequences of use, while questionnaire 2 asked about typical situations of use and applications of retrieved information. For this analysis, all questionnaires answered by pharmacists were evaluated using descriptive statistics. Results A total of 550 pharmacists completed online questionnaire 1, 87.3% of whom (n=480/550) worked in community pharmacies. Medication for cough and cold symptoms (19.3%, n=106/550) and non-opioid analgesics (16.9%, n=93/550) were most frequently inquired. 57.1% (n=314/550) reported that their risk perception of a given drug had changed after reading the respective fact sheet. Pharmacists' mean rating of fact sheet comprehensibility was 9.25 (Likert scale from 0 to 10). 79 pharmacists completed online questionnaire 2. 93.7% (n=74/79) considered embryotox.de helpful for informing and, if necessary, reassuring worried patients. They also used embryotox.de to pass on selected information to patients (79.7%, n=63/79), to check prescription drugs before dispensing (57.0%, n=45/79) and to consult with prescribing doctors in cases of critical medications (58.2%, n=46/79). Conclusion Community pharmacists obtain relevant information from embryotox.de on risk and safety of OTC and prescription drugs in pregnancy and lactation. Embryotox.de thus supports pharmacists in counselling pregnant and breastfeeding patients and ensuring safe and rational drug treatment.

Because of their developmental toxicity, some antiseizure medication (ASM) should be avoided during pregnancy. This may lead to discontinuation or switching of ASM after recognition of pregnancy, but some of these changes may be suboptimal. Trends in ASM use at conception were analyzed in 3,763 pregnancies prospectively ascertained by a teratology information service in Germany between 2000 and 2018. Focusing on women with epilepsy (n = 2,395), changes of treatment pattern during the 1st trimester were evaluated. There was an increase in women using ASMs for non-epilepsy indications from 19% in 2000 to 39% in 2018. Although a shift from non-recommended teratogenic ASMs to recommended ASMs was observed, 13% of women were still receiving non-recommended ASMs in early pregnancy at the end of the study period. Among women with epilepsy, ASM regimen remained unchanged during the 1st trimester in 90%, 6% switched to other ASMs, and only 4% discontinued. Valproate, oxcarbazepine, and topiramate were more likely to be discontinued or switched than other ASMs. This first analysis of treatment pattern in ASM exposed pregnancies in Germany confirms the general trend towards less teratogenic and newer ASMs. However, it remains questionable whether women still using non-recommended ASMs are refractory to lower-risk ASMs or disregard treatment guidelines and risk minimization measures.

The aetiology of congenital anomalies is often difficult to assess. Genetic abnormalities can play a role or exogenous factors such as maternal medication during pregnancy. Observational studies require reliable data on both gestational time and dosage of drug exposure during pregnancy and, if applicable, on precise description of congenital anomalies in the infant. The Berlin Embryotox Centre carried out a questionnaire-based project to investigate whether longer follow-up periods after birth lead to more accurate diagnoses of congenital anomalies. The Berlin Embryotox Centre offers risk assessment on medication during pregnancy to health care providers and pregnant women. Follow-up questionnaires asking for course and outcome of pregnancy are routinely sent out 8 weeks after the estimated date of birth. In this project, three additional questionnaires were sent to women with a singleton live-born infant, asking for paediatric findings documented along routine examinations offered to all children in Germany at the age of approximately 6 months (U5), 1 year (U6) and 2 years (U7). In addition, parents were asked to report their observations on the child’s development. Data were collected between March 2019 and May 2024. A total of 3719 parents completed at least one of the three additional follow-up questionnaires. Results of the standard questionnaire 8 weeks after birth showed 138 infants with a major defect and 13 with a genetic disorder. At the end of the extended follow-up period, 180 children were reported to have a major birth defect and 39 a genetic disorder. The rate of major birth defects increased from 3.7

Das Internetportal embryotox.de informiert evidenzbasiert, kostenlos und industrieunabhängig zur Arzneimitteltherapiesicherheit in Schwangerschaft und Stillzeit. Es wird von mehr als fünf Millionen Nutzer*innen pro Jahr besucht. Im Rahmen einer durch den G-BA Innovationsfonds geförderten Mixed-Methods-Studie wurde die Funktion von embryotox.de in der Versorgungspraxis untersucht. Diese Teilauswertung konzentriert sich auf die Nutzung durch die Apothekerschaft. Die Datenerhebung erfolgte mittels zweier Online-Fragebögen (Multiple-Choice-Antworten oder Likert-Skala von 0=„überhaupt nicht“ bis 10=„vollständig“). Der erste Fragebogen enthielt Fragen zu Nutzercharakteristika, klinischer Situation, Verständlichkeit der Arzneimittelinformationen und Konsequenzen der Nutzung, im zweiten wurden typische Situationen der Nutzung und Verwendung der abgerufenen Informationen erfragt. Für die vorliegende Teilanalyse wurden alle von Apotheker*innen beantworteten Fragebögen mittels deskriptiver Statistik ausgewertet. Insgesamt 550 Apotheker*innen füllten Online-Fragebogen 1 aus, davon arbeiteten 87,3% (n=480/550) in öffentlichen Apotheken. Am häufigsten wurde zu Medikamenten gegen Husten und Erkältungssymptome (19,3%, n=106/550) recherchiert sowie zu nicht-opioiden Analgetika (16,9%, n=93/550). Bei 57,1% (n=314/550) änderte sich durch diese Recherche die Risikobewertung des Arzneimittels. Die Verständlichkeit der Informationen wurde im Durchschnitt mit 9,25 (Likert-Skala von 0 bis 10) bewertet. 79 Apotheker*innen füllten Online-Fragebogen 2 aus. 93,7% (n=74/79) fanden embryotox.de hilfreich, um verunsicherte Patientinnen zu informieren und gegebenenfalls zu beruhigen. Weiterhin nutzten sie embryotox.de, um ausgewählte Informationen an Patientinnen weiterzugeben (79,7%, n=63/79), um ärztlich verordnete Medikamente vor der Abgabe zu überprüfen (57,0%, n=45/79) und um bei kritischen Arzneimitteln Rücksprache mit verschreibenden Ärztinnen bzw. Ärzten zu halten (58,2%, n=46/79). Apotheker*innen informieren sich zur Verträglichkeit in Schwangerschaft und Stillzeit bei embryotox.de sowohl zu rezeptfreien Präparaten (v. a. gegen akute Beschwerden) als auch zu verordneten Arzneimitteln. Damit üben sie eine wichtige Kontroll- und Beratungsfunktion bei der Arzneimittelversorgung Schwangerer und Stillender aus, die durch embryotox.de wesentlich unterstützt wird.

Tumor necrosis factor inhibitors (TNFi) are often used in the treatment of autoimmune diseases. Their use during pregnancy, particularly in the 2nd half, has been a matter of debate due to a potential risk of severe infections in infants. We aimed to describe (i) the dispensation of TNFi before and during pregnancy and (ii) the occurrence of hospitalizations with infections among prenatally exposed infants. Using the GePaRD database (claims data covering 20

Although use of inhibitors of the renin–angiotensin–aldosterone system (RAAS-I) is contraindicated in the second and third trimesters of pregnancy, a relevant number of pregnancies is still exposed. Fetopathy in children exposed after gestational week (GW) 20 is well described, but data on long-term outcomes are scarce. Our study aims to describe postnatal and long-term outcomes after fetal exposure to RAAS-I. We included all pregnancies in the German Pharmacoepidemiological Research Database GePaRD (claims data; 20

Background: Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used during pregnancy. Due to their fetotoxicity, NSAIDs are contraindicated during the third trimester. There is ongoing controversy about the extent to which NSAIDs may cause cardiovascular and renal impairment in the fetus earlier in the second trimester. Paracetamol, used as an effective treatment for closure of patent ductus arteriosus (PDA) after birth, is suspected to cause similar but unwanted effects during the third trimester of pregnancy. Methods: Three major pharmacovigilance databases (VigilanceCentral, EudraVigilance, and VigiBase) were searched for Individual Case Safety Reports (ICSRs; n = 1288) on fetotoxic effects that have been shown to result from NSAID exposure in late pregnancy. Results: In 219/1288 cases, an NSAID and/or paracetamol was taken after the first trimester, and the ICSR was not related to other reported risk factors. Out of these 219 ICSRs, 48 were exposed to NSAIDs in the second but not the third trimester or to paracetamol in the third trimester. Causality assessment was “probable or likely” in four NSAID reports and none of the paracetamol reports. Conclusions: The scarcity of adverse drug reactions (ADRs) in our study and in the literature, despite decades of pharmaceutical marketing and worldwide use of paracetamol as an analgesic of choice in the third trimester and the absence of formal contraindications against NSAIDs in the second trimester, speaks against a substantial cardiovascular and nephrotoxic risk of temporary use of NSAIDs in the second trimester or paracetamol in the third trimester. NSAIDs continue to be contraindicated in the third trimester.

PURPOSE:In analyzing pregnancy data concerning drug exposure in the first trimester, the risk of spontaneous abortions is of primary interest. For estimating the cumulative incidence function, the Aalen-Johansen estimator is typically used, and competing risks such as induced abortion and livebirth are considered. However, the delayed study entry can lead to overly small risk sets for the first events. This results in large jumps in the estimated cumulative incidence function of spontaneous abortions or induced abortions using the Aalen-Johansen estimator, and consequently in an overestimation of the probability. METHODS:Several approaches account for early overly small risk sets. The first approach is conditioning on the event time being greater than the event time causing the large jump. Second, the events can be ignored by censoring them. Third, the events can be postponed until a large enough number is at risk. These three approaches are compared. RESULTS:All approaches are applied using data of 54 lacosamide-exposed pregnancies. The Aalen-Johansen estimate of the probability of spontaneous abortion is 22.64%, which is relatively large for only three spontaneous abortions in the dataset. The conditional approach and the ignore approach have an estimated probability of 7.17%. In contrast, the estimate of the postpone approach is 16.45%. In this small sample, bootstrapped confidence intervals seem more accurate. CONCLUSIONS:In the analyses of pregnancy data with rare events, the postpone approach is favorable as no events are excluded. However, the approach that ignores early events has the narrowest confidence interval.

Effects of valproate (VPA) dose and treatment discontinuation during the first trimester of pregnancy on the risks of spontaneous abortions (SAB) and major birth defects were analyzed. Pregnancies with first trimester VPA exposure (n = 484) prospectively recorded by the German Embryotox center in 1997–2016 were compared with a randomly selected, non-exposed cohort (n = 1446). The SAB risk was not significantly increased in the VPA cohort [HRadj 1.31 (95% CI 0.85–2.02)] but major birth defects were significantly more frequent [8.7% vs. 3.4%; ORadj 2.61 (95% CI 1.51–4.50)]. Risk was even higher in pregnancies with no VPA discontinuation in first trimester [ORadj 3.66 (95% CI 2.04–6.54)]. Significant ORs were found for nervous system defects in general [ORadj 5.69 (95% CI 1.73–18.78)], severe microcephaly [ORadj 6.65 (95% CI 1.17–37.68)], hypospadias [ORadj 19.49 (95% CI 1.80–211)] and urinary system defects [ORadj 6.51 (95% CI 1.48–28.67)]. VPA dose had a stronger effect than antiepileptic poly- versus monotherapy; for VPA dose ≥ 1500 mg/day the ORadj was 5.41 (95% CI 2.32–12.66)]. A daily dose increase of 100 mg was calculated to raise the risk for major birth defects by 15% [OR 1.15 (95% CI 1.08–1.23)]. Overall, maternal first trimester treatment regimen had a relevant impact on birth defect risk.