European Journal of Clinical Pharmacology

, Volume 74, Issue 2, pp 171–179 | Cite as

Drug safety in pregnancy: the German Embryotox institute

Special Article
  • 288 Downloads

Abstract

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.

Keywords

Pharmacovigilance Pregnancy Teratogens Risk assessment 

Notes

Acknowledgements

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Vargesson N (2015) Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C Embryo Today 105(2):140–156.  https://doi.org/10.1002/bdrc.21096 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Physicians’ desk reference 71st ed. (2017). PDR network, Montvale, New Jersey, USAGoogle Scholar
  3. 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. 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. 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
  6. 6.
    Ornoy A (2009) Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol 28(1):1–10.  https://doi.org/10.1016/j.reprotox.2009.1002.1014 CrossRefPubMedGoogle Scholar
  7. 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
  8. 8.
    Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E, Kalviainen R, Trinka E (2015) Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia 56(7):1006–1019.  https://doi.org/10.1111/epi.13021 CrossRefPubMedGoogle Scholar
  9. 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. 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/
  11. 11.
    Epstein RA, Moore KM, Bobo WV (2015) Treatment of bipolar disorders during pregnancy: maternal and fetal safety and challenges. Drug Healthc Patient Saf 7:7–29.  https://doi.org/10.2147/DHPS.S50556 eCollection 52015PubMedGoogle Scholar
  12. 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
  13. 13.
    Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK, de Jong-van den Berg LT (2010) Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 362(23):2185–2193.  https://doi.org/10.1056/NEJMoa0907328 CrossRefPubMedGoogle Scholar
  14. 14.
    Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW Jr, Lott IT et al (1985) Retinoic acid embryopathy. N Engl J Med 313(14):837–841CrossRefPubMedGoogle Scholar
  15. 15.
    Henry D, Dormuth C, Winquist B, Carney G, Bugden S, Teare G, Levesque LE, Berard A, Paterson JM, Platt RW (2016) Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. CMAJ 188(10):723–730.  https://doi.org/10.1503/cmaj.151243 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zomerdijk IM, Ruiter R, Houweling LM, Herings RM, Sturkenboom MC, Straus SM, Stricker BH (2014) Isotretinoin exposure during pregnancy: a population-based study in The Netherlands. BMJ Open 4(11):e005602.  https://doi.org/10.1136/bmjopen-002014-005602 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Dai WS, LaBraico JM, Stern RS (1992) Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 26(4):599–606CrossRefPubMedGoogle Scholar
  18. 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
  19. 19.
    Barr M Jr (1994) Teratogen update: angiotensin-converting enzyme inhibitors. Teratology 50(6):399–409CrossRefPubMedGoogle Scholar
  20. 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
  21. 21.
    Dathe K, Beck E, Schaefer C (2016) Pregnancy outcome after chelation therapy in Wilson disease. Evaluation of the German Embryotox Database. Reprod Toxicol 65:39–45.  https://doi.org/10.1016/j.reprotox.2016.1006.1015 CrossRefPubMedGoogle Scholar
  22. 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
  23. 23.
    Huttel E, Padberg S, Meister R, Beck E, Schaefer C (2017) Pregnancy outcome of first trimester exposure to the vitamin K antagonist phenprocoumon depends on duration of treatment. Thromb Haemost 117(5):870–879.  https://doi.org/10.1160/TH1116–1111-0838 CrossRefPubMedGoogle Scholar
  24. 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. 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. 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
  27. 27.
    Borrell A, Stergiotou I (2013) Miscarriage in contemporary maternal-fetal medicine: targeting clinical dilemmas. Ultrasound Obstet Gynecol 42(5):491–497.  https://doi.org/10.1002/uog.12442 CrossRefPubMedGoogle Scholar
  28. 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
  29. 29.
    Beck E, Lechner A, Schaefer C (2017) Who seeks Teratology Information Service’s advice? Assessing the risk of selection bias in observational cohort studies on drug risks in pregnancy. Reprod Toxicol 67:79–84.  https://doi.org/10.1016/j.reprotox.2016.1011.1019 CrossRefPubMedGoogle Scholar
  30. 30.
    Meister R, Schaefer C (2008) Statistical methods for estimating the probability of spontaneous abortion in observational studies—analyzing pregnancies exposed to coumarin derivatives. Reprod Toxicol 26(1):31–35.  https://doi.org/10.1016/j.reprotox.2008.1006.1006 CrossRefPubMedGoogle Scholar
  31. 31.
    Bower C, Rudy E, Callaghan A, Quick J, Nassar N (2010) Age at diagnosis of birth defects. Birth Defects Res A Clin Mol Teratol 88(4):251–255.  https://doi.org/10.1002/bdra.20658 PubMedGoogle Scholar
  32. 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

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Pharmakovigilanz- und Beratungszentrum für EmbryonaltoxikologieInstitut für Klinische Pharmakologie und ToxikologieBerlinGermany

Personalised recommendations