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Tim Bothe,1 Anne-Katrin Fietz,2 Elke Schaeffner,1 Antonios Douros,3– 5 Anna Pöhlmann,2 Nina Mielke,1 Cédric Villain,1,6 Muhammad Helmi Barghouth,1 Volker Wenning,7 Natalie Ebert1 1Institute of Public Health, Charité – Universitätsmedizin Berlin, Berlin, Germany; 2Institute of Biometry and Clinical Epidemiology, Charité – Universitätsmedizin Berlin, Berlin, Germany; 3Departments of Medicine and of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada; 4Institute of Clinical Pharmacology and Toxicology, Charité – Universitätsmedizin Berlin, Berlin, Germany; 5Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada; 6Normandie Univ UNICAEN, INSERM U1075 COMETE, service de Gériatrie, CHU de Caen, Caen, France; 7AOK Nordost – Die Gesundheitskasse, Potsdam, GermanyCorrespondence: Tim Bothe, Charité – Universitätsmedizin Berlin, Institute of Public Health, Charitéplatz 1, Berlin, DE-10117, Germany, Tel +49 30 450 570054, Email tim.bothe@charite.dePurpose: The validity of ICD-10 diagnostic codes for chronic kidney disease (CKD) in health claims data has not been sufficiently studied in the general population and over time.Patients and Methods: We used data from the Berlin Initiative Study (BIS), a prospective longitudinal cohort of community-dwelling individuals aged ≥ 70 years in Berlin, Germany. With estimated glomerular filtration rate (eGFR) as reference, we assessed the diagnostic validity (sensitivity, specificity, positive [PPV], and negative predictive values [NPV]) of different claims-based ICD-10 codes for CKD stages G3-5 (eGFR < 60mL/min/1.73m²: ICD-10 N18.x-N19), G3 (eGFR 30–< 60mL/min/1.73m²: N18.3), and G4-5 (eGFR < 30mL/min/1.73m²: N18.4– 5). We analysed trends over five study visits (2009– 2019).Results: We included data of 2068 participants at baseline (2009– 2011) and 870 at follow-up 4 (2018– 2019), of whom 784 (38.9%) and 440 (50.6%) had CKD G3-5, respectively. At baseline, sensitivity for CKD in claims data ranged from 0.25 (95%-confidence interval [CI] 0.22– 0.28) to 0.51 (95%-CI 0.48– 0.55) for G3-5, depending on the included ICD-10 codes, 0.20 (95%-CI 0.18– 0.24) for G3, and 0.36 (95%-CI 0.25– 0.49) for G4-5. Over the course of 10 years, sensitivity increased by 0.17 to 0.29 in all groups. Specificity, PPVs, and NPVs remained mostly stable over time and ranged from 0.82– 0.99, 0.47– 0.89, and 0.66– 0.98 across all study visits, respectively.Conclusion: German claims data showed overall agreeable performance in identifying older adults with CKD, while differentiation between stages was limited. Our results suggest increasing sensitivity over time possibly attributable to improved CKD diagnosis and awareness.Keywords: CKD, diagnostic validity, health claims data, sensitivity, specificity

Rationale & Objective: The benefits of kidney transplantation compared to treatment with dialysis, including in older adult, are primarily limited by the number of donated kidneys. We studied the potential to expand the use of older living kidney donors., Study Design: Secondary analysis of the Berlin Initiative Study, a population-based cohort., Setting: & Participants: 2069 adults aged ≥70 years in Germany., Exposures: Age and sex., Outcomes: Suitability for living donation assessed by the absence of kidney-related exclusions for donation including albuminuria and low estimated glomerular filtration rate (eGFR) as well as absence of other medical exclusions. Willingness for living and deceased kidney donation assessed by participant survey., Analytical Approach: Descriptive analysis., Results: Among the 2069 participants (median age 80 years, 53% women, median eGFR 63 ml/min/1.73m 2 ), 93% had ≥1 medical contraindication for living donation at study entry unrelated to eGFR or albuminuria. Using two published eGFR and albuminuria thresholds for donor acceptance, 38% to 54% of participants had kidney-related exclusions for donation. Among the 5% to 6% of participants with neither medical nor kidney-related exclusions for living donation at baseline, 11% to 12% remained suitable for donation during 8 years of follow-up. Willingness for living or deceased donation was high (73% and 60%, respectively)., Limitations: GFR was not measured and medical exclusions unrelated to eGFR and albuminuria were assessed using a cohort database complemented by claims data., Conclusions: One in twenty older adults were potentially suitable for living kidney donation and willingness for living donation was high. Further studies are warranted to define the feasibility of expanding living kidney donation among older adults., (Copyright © 2024. Published by Elsevier Inc.)

Background: Frailty and polypharmacy are common conditions in older adults, especially in those with chronic kidney disease (CKD). Therefore, we analyzed the association of polypharmacy and incident frailty and the effect modification by CKD in very old adults., Methods: In non-frail individuals within the Berlin Initiative (cohort) Study, polypharmacy (≥ 5 medications) was assessed according to multiple definitions based on the number of regular and on demand prescription and over the counter drugs, as well as vitamins and supplements. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73m 2 and/or an albumin-creatinine ratio ≥ 30 mg/g. Incident frailty was assessed at follow-up using Fried criteria. Logistic regression was applied to assess (1) the association of different polypharmacy definitions with incident frailty and (2) effect modification by CKD., Results: In this cohort study, out of 757 non-frail participants (mean age 82.9 years, 52% female, 74% CKD), 298 (39%) participants reported polypharmacy. Over the observation period of 2.1 years, 105 became frail. Individuals with polypharmacy had 1.96 adjusted odds (95% confidence interval (CI): 1.20-3.19) of becoming frail compared to participants without polypharmacy. The effect of polypharmacy on incident frailty was modified by CKD on the additive scale (relative excess risk due to interaction: 1.56; 95% CI 0.01-3.12)., Conclusions: This study demonstrates an association of polypharmacy and incident frailty and suggests strong evidence for an effect modification of CKD on polypharmacy and incident frailty. Revision of prescriptions could be a target strategy to prevent frailty occurrence, especially in older adults with CKD., (© 2024. The Author(s).)

Background: Chronic kidney failure (CKF) is often treated with dialysis, which is invasive and costly and carries major medical risks. The existing studies of patients with CKF requiring dialysis that are based on claims data from German statutory health insurance (SHI) carriers employ varying definitions of this entity, with unclear consequences for the resulting statistical estimates., Methods: We carried out a cohort study on four random samples, each consisting of 62 200 persons aged 70 or above, from among the insurees of the SHI AOK Nordost, with one sample for each of the years 2012, 2014, 2016, and 2018. The prevalence, incidence, mortality, and direct health care costs of CKF requiring dialysis were estimated and compared on the basis of four different definitions from literature and a new definition developed by the authors in reference to billing data., Results: The different definitions led to variation in 12-month prevalences (range: 0.33-0.61%) and 6-month incidences (0.058-0.100%). The percentage of patients with prior acute kidney injury (AKI) ranged from 27.6% to 61.8%. Among incident patients, three-month survival ranged from 70.2% to 88.1%, and six-month survival from 60.5% to 81.3%. In CKF patients without prior AKI, the survival curves differed less across definitions (80.2-91.8% at three months, 70.7-84.4% at six months). The monthly health care costs ranged from €6010 to €9606, with marked variability across definitions in the costs of inpatient and outpatient care., Conclusion: The lack of a standardized definition of CKF requiring dialysis in German SHI claims data leads to variability in the estimated case numbers, mortality, and health care costs. These differences are most probably in part due to the variable inclusion of inpatients who received short-term dialysis after AKI.

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 [HR adj 1.31 (95% CI 0.85-2.02)] but major birth defects were significantly more frequent [8.7% vs. 3.4%; OR adj 2.61 (95% CI 1.51-4.50)]. Risk was even higher in pregnancies with no VPA discontinuation in first trimester [OR adj 3.66 (95% CI 2.04-6.54)]. Significant ORs were found for nervous system defects in general [OR adj 5.69 (95% CI 1.73-18.78)], severe microcephaly [OR adj 6.65 (95% CI 1.17-37.68)], hypospadias [OR adj 19.49 (95% CI 1.80-211)] and urinary system defects [OR adj 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 OR adj 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., (© 2024. The Author(s).)

Background: Secondary central nervous system lymphoma (SCNSL) confers a dismal prognosis and treatment advances are constrained by the lack of prospective studies and real-world treatment evidence., Methods: Patients with SCNSL of all entities were included at first diagnosis and patient characteristics, treatment data, and outcomes were prospectively collected in the Secondary CNS Lymphoma Registry (SCNSL-R) (NCT05114330)., Findings: 279 patients from 47 institutions were enrolled from 2011 to 2022 and 243 patients (median age: 66 years; range: 23-86) were available for analysis. Of those, 49 (20 %) patients presented with synchronous (cohort I) and 194 (80 %) with metachronous SCNSL (cohort II). The predominant histology was diffuse large B-cell lymphoma (DLBCL, 68 %). Median overall survival (OS) from diagnosis of CNS involvement was 17·2 months (95 % CI 12-27·5), with longer OS in cohort I (60·6 months, 95 % CI 45·5-not estimable (NE)) than cohort II (11·4 months, 95 % CI 7·8-17·7, log-rank test p < 0.0001). Predominant induction regimens included R-CHOP/high-dose MTX (cohort I) and high-dose MTX/cytarabine (cohort II). Rituximab was used in 166 (68 %) of B-cell lymphoma. Undergoing consolidating high-dose therapy and autologous hematopoietic stem cell transplantation (HDT-ASCT) in partial response (PR) or better was associated with longer OS (HR adjusted 0·47 (95 % CI 0·25-0·89), p = 0·0197)., Interpretation: This study is the largest prospective cohort of SCNSL patients providing a comprehensive overview of an international real-world treatment landscape and outcomes. Prognosis was better in patients with SCNSL involvement at initial diagnosis (cohort I) and consolidating HDT-ASCT was associated with favorable outcome in patients with PR or better., Competing Interests: Declaration of Competing Interest U.Ke. served in an advisory role for BMS/ Celgene, Takeda, Janssen, Gilead/ Kite, Roche, Abbvie, AstraZeneca, Novartis, Lilly, Pentixapharm and received travel support from BMS/ Celgene, Takeda, Janssen, Roche, Abbvie, Gilead/ Kite, AstraZeneca, Novartis, Lilly, Pentixapharm. S.H. served in an advisory role for Pentixapharm. Ro.S. served in an advisory role for BMS/ Celgene, Janssen, Gilead/ Kite, and Novartis. M.S-H. has an advisory role for Celgene GmbH, Amgen GmbH, Gilead/ Kite, Sanofi-Aventis, Glaxo Smith Kline, Bristol Myers Squibb, Shionogi and received financial support from Janssen-Cilag, Takeda, Novartis, Pfizer, Roche, Vifor Pharma, Celgene. P.L.R. received payment from Novartis, MSD, Abbvie, Roche, Incyte, Janssen-Cilag and travel support from Abbvie, Novartis, BMS, Janssen-Cilag and Roche. K.J. received royalties from Elsevier and Wolters Kluwer, obtained consulting fees and honoraria from Amgen, art tempi, Astra Zeneca, BD Solutions, Helsinn, Hexal, Karyopharm med update GmbH, MSD, Mundipharma, onkowissen, Riemser, Roche, Shire (Takeda), Vifor Pharma and Voluntis, B.C. received research grants from Gilead, received honoraria from BMS, Astra Zeneca, Gilead, Roche, Sandoz, Incyte, Abbvie and received travel support from Roche and Gilead. St. S. received research grants from Protherics Medicines Development Ltd., served in an advisory role for AMGEN, Gilead Sciences, Pfizer, SERB SAS, received honoraria from Akademie für Infektionsmedizin e.V., AMGEN, AVIR Pharma, CSi Hamburg GmbH, Gilead Sciences, Labor28, Novartis, Persberg Group GmbH/DGIM e.V., Pfizer, Vivantes GmbH and received travel support from Gilead Sciences and Novartis. A.K. Received financial support from Riemser. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Levetiracetam is increasingly used in pregnant women with epilepsy. Although teratogenic effects have not been observed so far, data on the risks of spontaneous abortion and major birth defects are still limited, especially for the frequently used dual therapy of levetiracetam and lamotrigine. Our primary aim was to analyze rates of major birth defects and spontaneous abortion after maternal levetiracetam treatment., Methods: This was a cohort study based on pregnancies recorded by the Embryotox Center from 2000 to 2017. Outcomes of prospectively ascertained pregnancies with first trimester levetiracetam monotherapy (n = 221) were compared to pregnancies with lamotrigine monotherapy for epilepsy (n = 469). In addition, all pregnancies with levetiracetam (n = 364) exposure during the first trimester were analyzed in comparison to a nonexposed cohort (n = 729). Pregnancies with the most frequently used combination therapy comprising levetiracetam and lamotrigine (n = 80) were evaluated separately., Results: There was no significantly increased risk of major birth defects or of spontaneous abortions after first trimester exposure to levetiracetam. Birth weight of male neonates was significantly lower after levetiracetam monotherapy compared to lamotrigine monotherapy. Dual therapy with levetiracetam and lamotrigine resulted in a significantly increased risk of spontaneous abortion (adjusted hazard ratio = 3.01, 95% confidence interval [CI] = 1.43-6.33) and a nonsignificant effect estimate for major birth defects (7.7%, n = 5/65, adjusted odds ratio = 1.47, 95% CI = .48-4.47) compared to a nonexposed cohort., Significance: Our study confirms the use of levetiracetam as a suitable antiepileptic drug in pregnancy. The lower birth weight of male neonates after maternal levetiracetam monotherapy and the unexpectedly high risk of spontaneous abortion and birth defects after dual therapy with levetiracetam and lamotrigine require further investigation., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: The Cockcroft-Gault equation (CrCl C-G ) is recommended for dose adjustment of direct oral anticoagulant drugs (DOACs) to kidney function. We aimed to assess whether defining DOAC dose appropriateness according to various kidney function estimators changed the associations between dose appropriateness and adverse events in older adults with atrial fibrillation (AF)., Methods: Participants of the Berlin Initiative Study with AF and treated with DOACs were included. We investigated CrCl C-G and estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration and European Kidney Function Consortium equations based on creatinine and/or cystatin C. Marginal structural Cox models yielded confounder-adjusted hazard ratios for the risk of mortality, thromboembolism and bleeding associated with dose status., Results: A total of 224 patients were included in the analysis (median age 87 years). Using CrCl C-G , 154 (69%) had an appropriate dose of DOACs, 52 (23%) were underdosed and 18 (8%) were overdosed. During a 39-month median follow-up period, 109 (14.9/100 person-years) participants died, 25 (3.6/100 person-years) experienced thromboembolism and 60 (9.8/100 person-years) experienced bleeding. Dose status was not associated with mortality and thromboembolism, independent of the equation. Underdose status was associated with a lower risk of bleeding with all the equations compared with the appropriate dose group. In participants with discrepancies in dose status using CrCl C-G and eGFR equations, the occurrence of endpoints did not differ between participants having an appropriate dose using CrCl C-G or eGFR., Conclusion: In older adults with AF, the association of DOAC dose status with adverse events did not differ when using CrCl C-G or eGFR. Our results suggest that eGFR equations are not inferior to CrCl C-G within this context., Competing Interests: N.E. received fees from Bayer AG Leverkusen as a member of an editorial advisory board outside the submitted work. E.S. received a research grant from Bayer unrelated to the topic of the article and receives a stipend from the National Kidney Foundation. The other authors declare no conflicts of interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: In older adults, epidemiological data on incidence rates (IR) of hospital-acquired acute kidney injury (AKI) are scarce. Also, little is known about trajectories of kidney function before hospitalization with AKI., Methods: We used data from biennial face-to-face study visits from the prospective Berlin Initiative Study (BIS) including community-dwelling participants aged 70+ with repeat estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C. Primary outcome was first incident of hospital-acquired AKI assessed through linked insurance claims data. In a nested case-control study, kidney function decline prior to hospitalization with and without AKI was investigated using eGFR trajectories estimated with mixed-effects models adjusted for traditional cardiovascular comorbidities., Results: Out of 2020 study participants (52.9% women; mean age 80.4 years) without prior AKI, 383 developed a first incident AKI, 1518 were hospitalized without AKI, and 119 were never hospitalized during a median follow-up of 8.8 years. IR per 1000 person years for hospital-acquired AKI was 26.8 (95% confidence interval (CI): 24.1-29.6); higher for men than women (33.9 (29.5-38.7) vs. 21.2 (18.1-24.6)). IR (CI) were lowest for persons aged 70-75 (13.1; 10.0-16.8) and highest for ≥ 90 years (54.6; 40.0-72.9). eGFR trajectories declined more steeply in men and women with AKI compared to men and women without AKI years before hospitalization. These differences in eGFR trajectories remained after adjustment for traditional comorbidities., Conclusion: AKI is a frequent in-hospital complication in individuals aged 70 + showing a striking increase of IR with age. eGFR decline was steeper in elderly patients with AKI compared to elderly patients without AKI years prior to hospitalization emphasising the need for long-term kidney function monitoring pre-admission to improve risk stratification., (© 2023. The Author(s).)

Introduction: Epilepsy is a common neurological disease requiring long-term therapy also during pregnancy. Most studies on pregnancy outcomes in women with epilepsy are based on antiseizure medication (ASM) in monotherapy. However, about 20-30% of epilepsy patients require polytherapy and newer ASMs are an option, when seizure control is not achieved with first line ASMs., Methods: Observational study evaluating the use of newer ASMs with marketing authorization since 2005 reported to the Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy between 2004 and 2019. In addition, course and outcome of lacosamide exposed pregnancies were analysed., Results: Our study confirms the increasing use of newer ASMs also in pregnant women. This is especially true for lacosamide, eslicarbazepine and brivaracetam with rising numbers of exposed pregnancies soon after marketing authorization. Analysis of 55 prospectively and 10 retrospectively ascertained lacosamide exposed pregnancies does not indicate increased risks of major birth defects or spontaneous abortion. However, bradycardia observed in 3 neonates might be related to prenatal lacosamide exposure., Conclusion: Available data do not support the assumption of lacosamide being a major teratogen. The increasing use of newer ASMs during pregnancy underscores the need for more studies to guide preconception counselling, especially for lacosamide, eslicarbazepine and brivaracetam., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

In contrast to other non-steroidal anti-inflammatory drugs (NSAIDs), naproxen use during pregnancy is not well studied. The objective of this analysis was to assess negative effects on pregnancy outcomes following naproxen exposure in the first trimester of pregnancy. Out of 121 exposed pregnancies prospectively recorded by two German teratology information services (TIS) 15 ended as spontaneous abortion and ten were electively terminated; in one case for prenatal diagnosis of anencephaly. Four pregnancies were stillborn, in these cases naproxen was discontinued more than two months before the event. Of 95 live-born infants, including three pairs of twins, two were born with major birth defects: one with dysmelia of the left hand and foot and another with a complex congenital heart defect, esophageal atresia with tracheoesophageal fistula, and choanal stenosis. The results of this case series do not suggest that naproxen has a significant teratogenic effect. However, due to the limited cohort size and lack of comparable reference group results should be interpreted with caution and better studied NSAIDs such as ibuprofen should be preferred in the first and second trimester of pregnancy. This work was supported by the German Federal Institute for Drugs and Medical Devices (BfArM)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The primary aim of our study was to assess pregnancy outcome after first-trimester exposure to fosfomycin., Methods: We performed an observational cohort study analysing prospectively ascertained pregnancies including 152 women exposed to fosfomycin in the first trimester of pregnancy in comparison with a randomly selected cohort comprising 456 pregnancies not exposed to fosfomycin. All pregnancies were identified through risk consultations using structured questionnaires between January 2000 and December 2016 by the German Embryotox pharmacovigilance institute in Berlin. Primary objectives were the risks of major birth defects and spontaneous abortion., Results: Only 1 out of 146 exposed infants was affected by a major birth defect (0.7%, 95% CI 0.04-4.33%) in comparison to 15/399 in the non-exposed cohort (3.8%, 95% CI 2.2-6.26%). Spontaneous abortions were observed in 5/152 cases in the fosfomycin cohort vs. 53/456 cases in the comparison cohort (cumulative incidence 6.2% vs. 23.1%; HR adjusted 0.35, 95% CI 0.14-0.90)., Conclusion: This is the first study specifically examining the teratogenic risk of fosfomycin. The study results do not indicate an increased risk of adverse pregnancy outcome after fosfomycin exposure during early pregnancy. However, larger studies are needed to confirm the safety of fosfomycin during the first trimester.

Purpose: Observational cohort studies are essential to evaluate the risk of adverse pregnancy outcomes associated with drug intake. Besides left truncation and competing events, it is crucial to account for the time-dynamic pattern of drug exposure. In fact, potentially harmful medications are often discontinued, which might affect the outcome. Ignoring these challenges may lead to biased estimation of drug-related risks highlighting the need for adequate statistical techniques., Methods: We reanalyze updated data of a recently published study provided by the German Embryotox pharmacovigilance institute. The aim of the study was to quantify the effect of discontinuation of vitamin K antagonist phenprocoumon on the risk of spontaneous abortion., Results: We outline multistate methodology as a powerful method removing bias in probability estimation inherent to commonly used crude proportions. We incorporate time-dependent discontinuation and competing pregnancy outcomes as separate states in a multistate model, which enables the formulation of hazard-based Cox proportional hazard models and the application of so-called landmark techniques. Results show that early discontinuation of phenprocoumon substantially reduces the risk of spontaneous abortion, which is of great importance for both pregnant women and treating physicians., Conclusions: An adequate handling of discontinuation times is essential when analyzing the risk of spontaneous abortion. The proposed concepts are not restricted to pregnancy outcome studies but have broad usage in other fields of epidemiology. Our nontechnical report may provide guidance for the design and analysis of future studies. Example code is provided., (© 2019 John Wiley & Sons, Ltd.)

Objectives: Beta-blockers are frequently used during pregnancy, with labetalol and metoprolol being considered as drugs of choice. As there are no prospective pregnancy studies for bisoprolol yet, our aim was to analyze pregnancy outcomes after bisoprolol exposure., Methods: Pregnancies exposed to bisoprolol during the first trimester were retrieved from the German Embryotox pharmacovigilance database. Pregnancy outcomes of prospectively ascertained pregnancies were compared with women neither exposed to beta-blockers nor other antihypertensives. In addition, retrospective reports on adverse drug reactions were screened for patterns of birth defects., Results: Inclusion criteria for the prospective study were met by 339 bisoprolol-treated women and 678 patients in the comparison cohort. Neither the risk for spontaneous abortions [adjusted hazard ratio (HRadj.) 1.06; 95% confidence interval (CI) 0.66-1.70] nor for major congenital malformations [adjusted odds ratio (ORadj.) 0.77; 95% CI 0.34-1.75] was increased after first trimester bisoprolol treatment. However, higher rates of preterm births [ORadj. 1.90; 95% CI 1.17-3.11] and reduced birthweights in singleton pregnancies (adjusted standard deviation score difference -0.48; 95% CI -0.62 to -0.34) were noted. Continued treatment with beta-blockers until birth was found to be associated with a higher risk for growth restriction than first trimester exposure only. A sensitivity analysis did not suggest higher rates of adverse pregnancy outcomes in hypertensive women on bisoprolol compared with nonhypertensive bisoprolol-exposed women., Conclusion: Our study supports the hypothesis that first trimester bisoprolol treatment does not increase the risk for spontaneous abortions or major birth defects. However, an influence of prolonged bisoprolol exposure on fetal growth cannot be ruled out.

Ibuprofen is an analgesic frequently used in the 1st and 2nd trimester of pregnancy. Most relevant studies deal with NSAID as a group and do not specifically focus on ibuprofen. In this study, 1117 women exposed to ibuprofen in the 1st trimester were compared to 2229 non-exposed women. Data were retrieved from the German Embryotox database. No significantly increased risk of major birth defects (4.8% vs. 4.1%; OR adjusted 1.11, 95% CI 0.75-1.64) or a distinct pattern of birth defects were found. The cumulative incidences of spontaneous abortions were similar across cohorts (15.5% vs. 16.6%; HR adjusted 0.85; 95% CI, 0.65-1.11). Subgroup analyses of pregnancies exposed for ≥7 (n = 223) and ≥30 days (n = 72) did not reveal a higher risk with increasing treatment duration. Ibuprofen does not seem to carry a substantial embryotoxic risk regarding the investigated endpoints., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Ongoing discussion about the safety of renin-angiotensin inhibitors in the first trimester and limited data on pregnancy outcomes after exposure to angiotensin AT1 receptor blockers (ARBs)., Methods: Observational cohort study compares outcomes of 215 prospectively ascertained pregnancies with first trimester exposure to ARBs with 642 non-hypertensive pregnancies., Results: The rate of major birth defects in the ARB cohort (9/168, 5.4%) was higher than in the comparison group (17/570, 3%), but not significantly increased (OR adj 1.9, 95% CI 0.7-4.9). There was no distinct pattern of anomalies among infants with birth defects. The risk of spontaneous abortions was not increased (HR adj 0.9, 95% CI 0.5-1.6), although the cumulative incidence was in the upper normal range (0.22, 95% CI 0.15-0.32). Higher rates of prematurity (OR adj 3.0; 95% CI 1.7-5.1) and a reduced birth weight after adjustment for sex and gestational age were observed. There was no evidence for an increased risk for major birth defects, spontaneous abortions, or preterm birth in a sensitivity analysis comparing ARB exposed hypertensive women to hypertensive women without ARB exposure during the first trimester., Conclusion: Our study supports the hypothesis that ARBs are not major teratogens. Patients inadvertently exposed to ARBs during the early pregnancy may be reassured. Nevertheless, women planning pregnancy should avoid ARBs. In selected cases, ARBs might be continued under careful monitoring of menstrual cycle and discontinued as soon as pregnancy is recognized.

Objectives: To analyze the risk of spontaneous abortions and major birth defects in pregnancies of women treated with angiotensin converting enzyme inhibitors (ACEIs) during the first trimester., Study Design: Observational cohort study of prospectively ascertained pregnancies from the German Embryotox pharmacovigilance institute. Pregnancy outcomes after maternal exposure to ACEIs during the first trimester were compared with pregnancies without antihypertensive treatment. In a sensitivity analysis, ACEI exposed hypertensive women were compared with hypertensive women on methyldopa., Results: The risk of spontaneous abortion among 329 ACEI exposed women was not increased compared to 654 women without antihypertensive treatment (adjusted hazard ratio 1.20, 95% confidence interval (CI) 0.74-1.92), whereas the risk for major birth defects (14/255; 5.5% vs. 19/567; 3.4%) was significantly increased (adjusted odds ratio 2.41, 95% CI 1.07-5.43). In contrast, birth defect rates were not significantly different between hypertensive women on ACEIs and hypertensive women on methyldopa. In addition, we did not observe a distinct pattern of birth defects among retrospectively ascertained pregnancies after ACEI exposure during the first trimester., Conclusions: Women with hypertension treated with ACEIs in early pregnancy are at higher risk for major birth defects, which may be explained by other factors associated with maternal hypertension. Women (inadvertently) exposed during early pregnancy may be reassured and treatment switched to antihypertensive drugs recommended for pregnancy., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Purpose: Cox-2-inhibitors (coxibs) are not recommended in pregnancy but early exposure may occur, for instance in unplanned pregnancies. Experience in pregnancy is limited leading to concerns in patients and their health care providers. Therefore, further data on coxibs and their effects on embryogenesis are needed., Methods: This observational cohort study evaluates pregnancies ascertained in Germany during the study period from January 2000 to January 2016. A cohort of 174 women exposed to coxibs in the first trimester was compared to a randomly selected cohort of 521 women without exposure to coxibs, other nonsteroidal anti-inflammatory drugs or known teratogens., Results: The overall rate of major birth defects was not significantly increased in the study cohort (2.9 vs. 2.7%, OR 1.08, 95% CI 0.34-3.42; OR adjusted 0.96, 95% CI 0.28-3.26). The cumulative incidence of spontaneous abortions was nonsignificantly lower in the exposed cohort (14.3 vs. 20.0%; HR, 0.90, 95% CI 0.51-1.58; HR adjusted, 0.87; 95% CI, 0.49-1.56). Elective terminations of pregnancies (ETOP), mainly for 'social' reasons, were more frequent in the coxib cohort (17.5 vs. 7.0%, HR, 2.31; 95% CI, 1.26-4.24; HR adjusted 2.12, 95% CI 1.13-3.97)., Conclusions: Our study results support the assumption that coxibs are not major teratogens. Considering the still limited evidence basis on coxib exposure during pregnancy, well-established alternatives should be preferred.

Published experience on first trimester exposure to methyldopa is still limited, although it is recommended as first-line treatment for hypertensive disorders in pregnancy in most countries. The primary aim of this prospective observational cohort study was to analyze the rate of major birth defects and spontaneous abortions in women with methyldopa therapy for chronic hypertension. Outcomes of 261 pregnancies with first trimester exposure to methyldopa and 526 comparison pregnancies without chronic hypertension reported to the German Embryotox pharmacovigilance institute were evaluated. The rate of major birth defects in the exposed cohort was not significantly increased compared with the comparison cohort (3.7% versus 2.5%; adjusted odds ratio, 1.24; 95% confidence interval, 0.4-4.0). There was a tendency toward a higher rate of spontaneous abortions in exposed women. The risk of preterm birth was significantly higher, and adjusted birth weight scores were significantly lower in the methyldopa group. Head circumferences were significantly reduced in exposed boys only. There was neither evidence for an increased risk for birth defects or increase in early pregnancy loss nor evidence for growth restriction or a reduced head circumference in a sensitivity analysis comparing monotherapies with methyldopa to metoprolol. However, the significantly increased risk of preterm birth in methyldopa-treated pregnancies was confirmed. In conclusion, our study does not indicate a teratogenic risk of methyldopa. Further studies are needed to confirm its safety in the first trimester and clarify the influence of hypertension and methyldopa on preterm birth and intrauterine growth., Clinical Trial Registration: URL: https://drks-neu.uniklinik-freiburg.de/drks&#95;web/. Unique identifier: DRKS00010502., (© 2017 American Heart Association, Inc.)