Drug safety in pregnancy: the German Embryotox institute
Since 1988, the German Embryotox institute combines individual counselling of pregnant women and their health care providers (HCP) with research on drug safety in pregnancy. In addition, Embryotox offers web-based information which covers the most important and most frequently requested pharmaceutical substances. In contrast to ready-made drug risk information in package leaflets and other product information, individual counselling considers different clinical settings such as (1) looking for a drug of choice or planning pregnancy under medication, (2) risk assessment of a particular drug that has already been taken during an (unplanned) pregnancy and (3) evaluation of an adverse pregnancy outcome in association with a particular medication. Using the three established developmental toxicants valproic acid, isotretinoin, and renin-angiotensin-aldosterone system (RAAS) inhibitors as an example, the need of detailed information is illustrated. Through the risk communication process, pregnancy outcome data are routinely collected by Embryotox. This approach uses the advantages of a pre-existing communication structure and of dealing with motivated responders. Engagement in the treatment plan facilitates receiving reliable data on drug exposure as well as detailed follow-up data. Based on these patient records, prospective datasets are evaluated in observational cohort studies in comparison to non-exposed control cohorts. In addition, retrospective datasets received as suspected adverse drug reactions from multiple German sources allow a screening for signals of teratogenicity and distinct patterns of developmental toxicity. Clinical expertise in specialties such as teratology, paediatrics, embryology, obstetrics and human genetics are required to ensure high-quality assessment of drug safety in pregnancy.
KeywordsPharmacovigilance Pregnancy Teratogens Risk assessment
We would like to thank all the staff from the German Embryotox institute for the counselling, documentation, data handling and statistical data evaluation. We also thank L. Pritchard for the linguistic review.
Our institute is supported by the German Federal Institute for Drugs and Medical Devices (BfArM) and the Berlin health ministry.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Physicians’ desk reference 71st ed. (2017). PDR network, Montvale, New Jersey, USAGoogle Scholar
- 3.European Medicines Agency, CHMP (2008) Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling, EMEA/CHMP/203927/2005, publication date 24/07/2008. http://www.ema.europa.eu
- 4.Food and Drug Administration, content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling, publication date 09/10/2014. http://federalregister.gov/a/2014-28241
- 5.Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW (2013) Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 12(3):244–252. https://doi.org/10.1016/S1474–4422(1012)70323-X CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Tomson T, Battino D, Perucca E (2016) Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet Neurol 15(2):210–218. https://doi.org/10.1016/S1474–4422(1015)00314–00312 CrossRefPubMedGoogle Scholar
- 9.European Medicines Agency (2014) PRAC recommends strengthening the restrictions on the use of valproate in women and girls, EMA/612389/2014, publication date 09/10/2014. http://www.ema.europa.eu/ema/
- 10.European Medicines Agency PRAC (2014) Assessment report, substances related to valproate, EMA/686022/2014, publication date 09/10/2014. http://www.ema.europa.eu/ema/
- 12.Tosato S, Albert U, Tomassi S, Iasevoli F, Carmassi C, Ferrari S, Nanni MG, Nivoli A, Volpe U, Atti AR, Fiorillo A (2017) A systematized review of atypical antipsychotics in pregnant women: balancing between risks of untreated illness and risks of drug-related adverse effects. J Clin Psychiatry 78(5):e477–e489. https://doi.org/10.4088/JCP.4015r10483 CrossRefPubMedGoogle Scholar
- 18.Schaefer C, Meister R, Weber-Schoendorfer C (2010) Isotretinoin exposure and pregnancy outcome: an observational study of the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy. Arch Gynecol Obstet 281(2):221–227. https://doi.org/10.1007/s00404–00009–01112-00402 CrossRefPubMedGoogle Scholar
- 20.Oppermann M, Padberg S, Kayser A, Weber-Schoendorfer C, Schaefer C (2013) Angiotensin-II receptor 1 antagonist fetopathy—risk assessment, critical time period and vena cava thrombosis as a possible new feature. Br J Clin Pharmacol 75(3):822–830. https://doi.org/10.1111/j.1365–2125.2012.04388.x CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Hoeltzenbein M, Beck E, Meixner K, Schaefer C, Kreutz R (2016) Pregnancy outcome after exposure to the novel oral anticoagulant rivaroxaban in women at suspected risk for thromboembolic events: a case series from the German Embryotox Pharmacovigilance Centre. Clin Res Cardiol 105(2):117–126. https://doi.org/10.1007/s00392–00015–00893-00395 CrossRefPubMedGoogle Scholar
- 24.Weber-Schoendorfer C, Oppermann M, Wacker E, Bernard N, Beghin D, Cuppers-Maarschalkerweerd B, Richardson JL, Rothuizen LE, Pistelli A, Malm H, Eleftheriou G, Kennedy D, Kadioglu Duman M, Meister R, Schaefer C (2015) Pregnancy outcome after TNF-alpha inhibitor therapy during the first trimester: a prospective multicentre cohort study. Br J Clin Pharmacol 80(4):727–739. https://doi.org/10.1111/bcp.12642 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Wacker E, Navarro A, Meister R, Padberg S, Weber-Schoendorfer C, Schaefer C (2015) Does the average drug exposure in pregnant women affect pregnancy outcome? A comparison of two approaches to estimate the baseline risks of adverse pregnancy outcome. Pharmacoepidemiol Drug Saf 24(4):353–360. https://doi.org/10.1002/pds.3744 CrossRefPubMedGoogle Scholar
- 26.European surveillance of congenital anomalies EUROCAT (uploaded data 07/04/2017) Prevalence dat tables, cases and prevalence (per 10,000 births) of all congenital anomaly subgroups for all registries, from 2011–2015. In, http://www.eurocat-network.eu/accessprevalencedata/prevalencetables ed
- 28.Voigt M, Rochow N, Schneider KT, Hagenah HP, Scholz R, Hesse V, Wittwer-Backofen U, Straube S, Olbertz D (2014) New percentile values for the anthropometric dimensions of singleton neonates: analysis of perinatal survey data of 2007–2011 from all 16 states of Germany. Z Geburtshilfe Neonatol 218(5):210–217. https://doi.org/10.1055/s-0034-1385857 CrossRefPubMedGoogle Scholar
- 32.Statistische Ämter des Bundes und der Länder Gebiet und Bevölkerung - Fläche und Bevölkerung, 31/12/2015. In, http://www.statistik-portal.de/Statistik-Portal/de_jb01_jahrtab1.asp ed