Ivabradine use in pregnant women—treatment indications and pregnancy outcome: an evaluation of the German Embryotox database

Purpose: Ivabradine has been approved for the treatment of chronic heart failure and chronic stable angina pectoris in Europe. Based on adverse outcomes of reproductive animal studies and the lack of human data, ivabradine is considered contraindicated during pregnancy. The aim of this observational study is to analyse ivabradine use before and during pregnancy. Methods: We evaluated all ivabradine-related requests to the German Embryotox Institute from 2007 to 2019. Exposed pregnancies were analysed as to their outcome. Results: Off-label use for supraventricular tachycardia was frequent in women of childbearing age. Of 38 prospectively ascertained pregnancies with ivabradine exposure and completed follow-up, 32 resulted in live births, 3 in spontaneous abortions, and 3 were electively terminated. One neonate presented with major birth defects (atrial septal defect and cleft palate). In 33/38 patients, ivabradine was discontinued after confirmation of pregnancy without cardiac deterioration and 5/38 women continued ivabradine throughout pregnancy. In addition, there were 3 retrospectively reported pregnancies including one major birth defect (tracheal atresia). Conclusion: This case series represents the largest cohort of ivabradine-exposed pregnancies, published so far. According to our findings, ivabradine appears not to be a major teratogen. However, established drugs of choice with strong evidence of low risk for the unborn should be preferred in women planning pregnancy. After inadvertent exposure during pregnancy or lack of treatment alternatives, fetal ultrasound for structural anomalies and growth restriction is recommended. In addition, close monitoring is necessary in pregnant women with supraventricular arrhythmias or cardiac disease

Fetal adverse effects following NSAID or metamizole exposure in the 2nd and 3rd trimester: an evaluation of the German Embryotox cohort

Background: Non-steroidal anti-inflammatory drugs (NSAID) are frequently used to treat pain, fever and inflammatory conditions. Due to evidenced fetotoxicity, treatment with NSAID and metamizole should be avoided in the 3rd trimester of pregnancy. There is an ongoing debate on fetotoxic risk of 2nd trimester use which is why we have conducted this study. Methods: In this observational cohort study outcome of pregnancies with NSAID and/or metamizole exposure in the 2nd and/or 3rd trimester (study cohort n = 1092) was compared with pregnancies exposed to NSAID and/or metamizole in the 1st trimester only (comparison cohort, n = 1154). The WHO-UMC system was used to assess causality between study medication and study endpoints. Prenatal study endpoints were constriction of ductus arteriosus Botalli, oligohydramnios, late spontaneous abortion (SAB) or stillbirth. Postnatal study endpoints were patent ductus arteriosus (PDA), anomalies of the right heart ventricle, primary pulmonary hypertension (PPHT), and neonatal impairment of kidney function. Results: Ductus arteriosus constriction was diagnosed in 5/1092 (0.5%) in the study cohort versus 0/1154 pregnancies in the comparison cohort. In one fetus, ductus arteriosus constriction and oligohydramnios occurred already in the late 2nd trimester after long-term NSAID exposure. Oligohydramnios was diagnosed in 41/1092 (3.8%) in the study cohort versus 29/1154 (2.5%) cases in the comparison cohort [RR, 1.5 (95% CI 0.9-2.4)]. Limited to 2nd trimester, oligohydramnios occurred in 8/904 (0.9%) versus 2/1154 (0.2%) pregnancies [RR, 5.1 (95% CI 1.1-24.0)]. At least in four of the 2nd trimester exposed pregnancies NSAID exposure lasted several weeks. Late SAB or stillbirth occurred in 14/1092 (1.3%) versus 17/1154 (1.5%). Postnatal cardiovascular or renal pathology did not differ between the cohorts. Conclusions: NSAID use in the 2nd trimester limited to a few days does not appear to pose a relevant risk. Use for longer periods in the advanced 2nd trimester, however, may cause oligohydramnios and ductus arteriosus constriction similar to effects observed after 3rd trimester use

Mutations in GDF5 Reveal a Key Residue Mediating BMP Inhibition by NOGGIN

Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to the BMP–inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling

Isolated hand malformations caused by molecular alterations affecting the BMP- pathway and SHH

Die Ausbildung der anatomischen Strukturen der Hand ist ein komplexer Prozess. Die Aktivität einer Vielzahl von Genen ist in der frühen Embryonalphase notwendig, um die regelrechte Handentwicklung zu gewährleisten. Dem BMP- Signalweg und der SHH-Signalwirkung kommt hierbei eine wesentliche Bedeutung zu. Im Rahmen dieser Arbeit konnte nachgewiesen werden, dass Mutationen in verschiedenen Molekülen des BMP-Signalwegs die Ursache von isolierten Handfehlbildungen darstellen. (1) So konnte mittels einer Positionsklonierung BMPR1B als merkmalsassoziiertes Gen für die Brachydaktylie Typ A2 identifiziert werden. Nachfolgend wurden bei betroffenen Personen die heterozygoten Punktmutationen p.I200K und p.R486W nachgewiesen, deren Pathogenität über weiterführende funktionelle Analysen bestätigt wurde. (2) In einem zweiten Projekt ist eine in BMPR1B liegende heterozygote Punktmutation p.R486Q näher analysiert worden. Diese Mutation ist klinisch mit einem ungewöhnlichen Phänotyp von kombinierter Brachydaktylie Typ C und proximalem Symphalangismus assoziiert. (3) Ein weiteres Projekt konnte die molekulare Ursache für eine Subgruppe der Brachydaktylie Typ B aufklären. Der Subtyp B2 wird durch Mutationen in NOG bedingt, wie durch den Nachweis von 6 verschiedenen heterozygoten Punktmutationen und anschließender funktioneller Beweisführung gezeigt wurde. Um in der Embryonalentwicklung der Hand eine exakte zeitliche und gewebespezifische Expression der bedeutsamen Gene zu gewährleisten, ist eine abgestimmte Regulation der Genaktivität nötig. Die Steuerung der Genexpression kann unter anderem über sog. cis-regulatorische Elemente erfolgen. In dieser Arbeit werden Duplikationen von cis-agierenden Elementen beschrieben, die über eine Dysregulation der Genaktivität von BMP2 und SHH die klinische Ausprägung von isolierten Handfehlbildungen bedingen. (4) Mit Hilfe einer lokusspezifische Array-CGH-Analyse wurde eine Mikroduplikation in einem nicht-kodierenden Bereich, der etwa 110 kb 3´ von BMP2 entfernt liegt, nachgewiesen. Diese Mikroduplikation korreliert klinisch mit einer Brachydaktylie Typ A2. Analysen an einem transgenen Mausmodel bestätigen, dass innerhalb des duplizierten Abschnittes ein Element zur extremitätenspezifischen Steuerung der BMP2-Expression lokalisiert ist. Eine Duplikation dieses cis-regulatorischen Elementes ist pathogen. (5) Desweiteren wurde über eine Array-CGH-Analyse eine Duplikation identifiziert, die das cis- lokalisierte Steuerungselement (ZRS) für die SHH-Expression in den Extremitäten umfasst. Das duplizierte ZRS geht in variabler Ausprägung mit Polysyndaktylie und triphalangealen Daumen einher und imitiert den Phänotyp, der auch durch in der ZRS liegende Punktmutationen verursacht wird. Die vorliegende Arbeit erweitert das Spektrum der phänotypischen Ausprägung sowie der molekularen Störungen von isolierten Handfehlbildungen und trägt über funktionelle Analysen zu dem Verständnis der zugrunde liegenden Pathogenese bei.The formation of hand anatomy is a complex process. A variety of genes are required to ensure the proper development in early embryogenesis. The BMP- pathway and SHH are both major players in programming the hand structures. This work shows that mutations in different molecules within the BMP-pathway lead to isolated hand malformations. (1) Positional cloning identified BMPR1B as the responsible gene for brachydactyly type A2. Two different heterozygous point mutations were found in affected patients, p.I200K and p.R486W. Subsequent functional studies proofed the pathogenicity of these mutations. (2) A second project focused on the heterozygous amino acid change p.R486Q in BMPR1B. This mutation is associated with an uncommon clinical phenotype of combined brachydactyly type C and proximal symphalangism. (3) In another project, the molecular cause of a subgroup of brachydactyly type B was identified. Six different heterozygous mutations in NOG were shown to be pathogenic resulting in the subtype B2. The chronology of embryonic hand development is controlled by an exact time- and tissue-dependent expression of relevant genes. Therefore, a fine-tuned regulation of gene activity is necessary i.e. by long-range cis-regulating elements. This work describes duplications of cis-regulators leading to a dysregulation in gene expression of BMP2 and SHH. These duplicated regulatory elements are associated with the presence of hand malformations. (4) In patients showing brachydactyly type A2 a heterozygous microduplication was identified about 110 kb 3´ of BMP2 by using locus specific array CGH analysis. This duplication is located in a non- coding region containing highly conserved sequences that argue for a long- range regulator of BMP2. A transgenic mouse model was created to test the latter hypothesis. The results suggest that BMP2 expression in the limb is regulated by a distant cis-acting enhancer located within the duplication. (5) Array CGH analysis was carried out in a family with variable polysyndactyly and triphalangeal thumbs. A microduplication including a limb specific cis- regulatory element (ZRS) for SHH expression was identified as the underlying cause. The observed hand phenotypes in this family resemble the phenotypic effects due to point mutations within the ZRS. The present work expands the spectrum of clinical characteristics and the molecular basis of hand malformations

Drug safety in pregnancy: the German Embryotox institute

Abstract Since 1988, the German Embryotox institute combinesindividual counselling of pregnant women and theirhealth care providers (HCP) with research on drug safety inpregnancy. In addition, Embryotox offers web-based informationwhich covers the most important and most frequentlyrequested pharmaceutical substances. In contrast to readymadedrug risk information in package leaflets and other productinformation, individual counselling considers differentclinical settings such as (1) looking for a drug of choice orplanning pregnancy under medication, (2) risk assessment of aparticular drug that has already been taken during an(unplanned) pregnancy and (3) evaluation of an adverse pregnancyoutcome in association with a particular medication.Using the three established developmental toxicants valproicacid, isotretinoin, and renin-angiotensin-aldosterone system(RAAS) inhibitors as an example, the need of detailed informationis illustrated. Through the risk communication process,pregnancy outcome data are routinely collected byEmbryotox. This approach uses the advantages of a preexistingcommunication structure and of dealing with motivatedresponders. Engagement in the treatment plan facilitatesreceiving reliable data on drug exposure as well as detailedfollow-up data. Based on these patient records, prospectivedatasets are evaluated in observational cohort studies in comparisonto non-exposed control cohorts. In addition, retrospectivedatasets received as suspected adverse drug reactionsfrom multiple German sources allow a screening for signalsof teratogenicity and distinct patterns of developmental toxicity.Clinical expertise in specialties such as teratology, paediatrics,embryology, obstetrics and human genetics are requiredto ensure high-quality assessment of drug safety in pregnancy.Keywords Pharmacovigilance . Pregnancy . Teratogens .Risk assessmen

Negligible risk of prenatal ductus arteriosus closure or fetal renal impairment after third‐trimester paracetamol use: evaluation of the German Embryotox cohort

Objective: Risk of fetotoxicity after paracetamol exposure in the third trimester. Design: Observational cohort study and retrospective case assessment. Setting: Germany, 2008-2017. Population: Pregnant women exposed to paracetamol. Methods: Prospectively enrolled third-trimester pregnancies that had been exposed to paracetamol (604) were compared with pregnancies exposed to paracetamol in the first and/or second trimester only (1192). Exclusion criteria were exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) in the second or third trimester. Additionally, the Embryotox 'adverse drug reaction in pregnancy' database was screened for cases of fetotoxicity. Main outcome measures: The prenatal study end points focused on narrowing or closure of ductus arteriosus Botalli, late fetal death, and oligohydramnios. The postnatal end points included patent ductus arteriosus (PDA), primary pulmonary hypertension (PPHT), and impaired renal function. Results: In both cohorts, no fetus with intrauterine narrowing or closure of the ductus arteriosus Botalli was reported (0/604 versus 0/1192). Oligohydramnios was diagnosed at a similar frequency in both cohorts: 1.3% (8/604) versus 1.6% (19/1192). There was one stillbirth in the study cohort (1/604, 0.2%) and four stillbirths in the comparison cohort (4/1192, 0.3%). The rates of PDA in neonates were similar: 0.7% (4/615) versus 0.7% (9/1212). PPHT as well as serious postnatal renal disorders were reported once in each cohort. In 12 out of 96 retrospective cases, there were indicators for study end points; however, co-exposure to NSAIDs or complex situations weaken the assumption of paracetamol toxicity. Conclusions: Fetal cardiovascular or renal toxicity of maternal third-trimester paracetamol use appears to be negligible. Tweetable abstract: Paracetamol use in the third trimester does not seem to be associated with a relevant risk of fetotoxicity

Estimating the Beginning of Pregnancy in German Claims Data: Development of an Algorithm With a Focus on the Expected Delivery Date

BACKGROUND: Estimating the beginning of pregnancy is crucial when studying drug safety in pregnancy, but important information in this regard, such as the last menstrual period (LMP), is generally not recorded in claims databases. The beginning of pregnancy is therefore usually estimated by subtracting a median length of pregnancy from the date of birth. Due to the variability in pregnancy lengths, this might result in non-negligible errors. German claims data may offer the possibility to estimate the beginning of pregnancy more precisely based on the expected delivery date (EDD) which can be coded once or more often during a pregnancy. PURPOSE: To estimate the beginning of pregnancy in German claims data focusing on the potential of the expected delivery date (EDD). METHODS: We included data of all pregnancies in women aged 12–50 years ending in a live birth between 2006 and 2015 identified in the German Pharmacoepidemiological Research Database (GePaRD). We assessed the number of coded EDDs per pregnancy and the concordance if ≥ 2 EDDs were coded. We estimated the beginning of pregnancy by subtracting 280 days from the EDD or the most frequent EDD (in case of discordant EDDs). To examine plausibility, we determined the distribution of pregnancy lengths and assessed whether the gestational age at which prenatal examinations were coded was plausible. For pregnancies without EDD, the beginning was estimated by subtracting the respective observed median lengths of pregnancy for preterm births, term births, and births after due date from the actual dates of birth. RESULTS: In 82.4% of pregnancies, at least one EDD was available (thereof 6.1% with only one EDD and 80.9% with ≥ 2 EDDs that were all concordant). The maximal difference between discordant EDDs was in median 5 days (interquartile range: 3–7 days). Based on the EDD, the median length of pregnancy was 276 days for term births and in 84.7% of pregnancies the second antibody screening test was performed in the recommended interval ± 2 weeks. In pregnancies without EDD the respective proportion was 84.9%. CONCLUSIONS: By using the EDD, the beginning of pregnancy can plausibly be estimated in German claims data

Investigating drug safety in pregnancy based on the German Pharmacoepidemiological Research Database (GePaRD): A proof-of-concept analysis on the association between valproate and spina bifida

PURPOSE: Large health-care databases are increasingly used for research on drug utilization and safety in pregnancy. For the German Pharmacoepidemiological Research Database (GePaRD), covering ~20% of the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof-of-concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child. METHODS: We identified all pregnancies in GePaRD between 2006 and 2016 in women aged 12 to 50 years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55 days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA-exposed ones to all pregnancies. RESULTS: Overall, we identified 1 271 384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA-exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval [CI]: 1.7–88.2). Out of 775 875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA-exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9–76.0). CONCLUSIONS: Our proof-of-concept analysis based on GePaRD showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of GePaRD and the developed algorithms to conduct studies on drug safety in pregnancy