Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium PROTECT Pregnancy Study: An Exploratory Study of Self-Reported Medication Use in Pregnant Women Prepared on behalf of the PROTECT Consortium by Nancy Dreyer1, Stella Blackburn1, Shahrul Mt-Isa2, Maja Laursen3, AP Zetstra-Van der Woude4, Jonathan Richardson5, Valérie Hliva2, Lynne Comiskey6 On behalf of PROTECT Work Package 4 (New Tools for Data Collection from Consumers) participants. 1 Quintiles Real World and Late Phase Research 2 School of Public Health, Imperial College London, United Kingdom 3 Statens Serum Institut, Denmark 4 University of Groningen, the Netherlands 5 Institute of Cellular Medicine, Newcastle University, United Kingdom 6 Genzyme a Sanofi Company Reviewed by PROTECT Work Package 4 participants Simon Thomas5, Lolkje de Jong-Van den Berg4, Omer de Mol6 Acknowledgements: We wish to acknowledge the collaboration of Alison Bourke, IMS Cegedim Strategic Data Medical Research, London, United Kingdom; Anna Latos-Bieleńska, Department of Medical Genetics, Poznan University of Medical Sciences; Bina Patel, Amgen; Christine Hallgreen, University of Copenhagen, Deborah Ashby, Imperial College London School of Public Health; Jens-Peter Balling, Lundbeck; Sally Stevens, Institute of Cellular Medicine, Newcastle University; Rebecca Johnson, International Alliance of Patients’ Organizations, London, United Kingdom Version 18.3 (1st September 2015) Disclaimer: The processes described and conclusions drawn from the work presented herein relate solely to the testing of methodologies and representations for the evaluation of benefit and risk of medicines. This report neither replaces nor is intended to replace or comment on any regulatory decisions made by national regulatory agencies, nor the European Medicines Agency Acknowledgements: The research leading to these results was conducted as part of the PROTECT consortium (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium, www.imi- protect.eu) which is a public-private partnership coordinated by the European Medicines Agency. The PROTECT project has received support from the Innovative Medicine Initiative Joint Undertaking (www.imi.europa.eu) under Grant Agreement n° 115004, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution 1 Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium Abstract The PROTECT Pregnancy Study was designed to pilot direct-to-patient data collection methods for use in postmarketing surveillance into the foetal effects of maternal medication use in pregnancy. This study which recruited women between October 2012 and January 2014 explored whether women in participating EU countries were willing to provide information via the internet to enable prospective collection of medication exposure data and information about other life style factors during pregnancy. The study’s main objective was to assess the extent to which data collected directly from pregnant women via the Internet and an interactive voice response system (IVRS) would provide information on medication use and other potential risk factors throughout pregnancy that is suitable for research purposes. Pregnant women were recruited for the study using a variety of methods and were asked about use of medications, alcohol and tobacco, recreational drugs, herbals and other factors that could negatively affect birth outcome. The pilot study revealed that women would indeed volunteer to provide information on medication and lifestyle factors during pregnancy, with 2521 women enrolling from four countries over 8-18 months. The four countries include the United Kingdom (UK), The Netherlands (NL), Denmark (DK) and Poland (PL). Of those who enrolled in the PROTECT pregnancy study, only 2066 provided any data, with all but one providing data via internet. Of the 2065 who provided data via the Internet, 23% were recruited during their first trimester of pregnancy, 52% in their second and 25% in their 3rd trimester, showing that it was indeed feasible, though more difficult, to recruit women early in pregnancy. Eighty-three percent of women used 1 or more medicines (range 0-16) during their pregnancy or in the preceding month, with 19% reporting using 5 or more different medications. Women reported using slightly more medications during the first trimester (36% reported using at least one medication), compared with the second (34%) and third (32%) trimesters. Comparing data reported from the women in PROTECT with their linked data (primarily in the Danish registers) revealed that 83% of self-reported medicines prescribed for chronic conditions that were also recorded in the national prescription medication register. Women also reported taking several drugs which were not in the register during or within the preceding pregnancy. Much of this “non-register” drug use may be explained by non-prescription drug use or use at hospital or medications purchased more than six months prior to pregnancy. Further, 24% of women reported taking non-prescription medications during pregnancy, not counting herbals and dietary supplements; seven percent reported using herbal products during pregnancy. These findings suggest that register or survey data alone will not give a complete and accurate reflection of total drug use during pregnancy since there is both a significant non-prescription medication use and a discrepancy between recorded and reported medicine use. Also, self-reported data contained quite a lot of valuable information on medicines used for short-term conditions and medications used intermittently. Overall about one percent of women reported that they had taken medications that were prescribed for others and given to them, and seven percent reported having decided not to take medications that had been prescribed for them. In addition, seven percent of women reported having received anaesthetics during pregnancy, and five percent reported exposure to x-rays. Pregnancy outcomes were provided by 464 out of 1555 women whose expected dates of delivery occurred while the study was still actively collecting data. Overall 91% of women who reported a pregnancy outcome had a live birth. Eight of these births were twins which corresponds to population based figures. The frequency of foetal loss before 22 weeks of pregnancy was highest in Denmark 15% compared with 0-8% in the other three countries. Since a 2 Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium higher percentage of women in Denmark than in other countries were recruited during the first trimester when foetal loss is highest, this result is not surprising. Ten mothers (2.3%) reported that their babies had a birth defect that was “visible” to them at birth. Since the question posed to mothers was about visible defects rather than any defect because we thought that none-visible birth defects might not be immediately detected, it is our interpretation that what we observed is close to the expected range as reported by clinicians. We also conducted a comparison of self-reported data with data from electronic health records in the UK but were only able to match a small number of records, which precluded much generalization. This pilot study has provided valuable insights into whether data collected directly from consumers are suitable for research purposes. We found that it was possible to recruit pregnant women without the direct intervention of health care professionals, but that paid advertisements were necessary to recruit a reasonable sample size in a relatively short period of time. We were also able to recruit women earlier in pregnancy than is generally possible using the more traditional methods of data collection. Respondents provided details of prescription medication use. They also reported non-prescription medicine use as well as herbal and homeopathic drug use – all of which have proved difficult to collect by other means. Women were also willing to provide details of life-style choices such as alcohol, smoking and recreational drug use which are frequently not accurate or non-existent in medical records. This means that information on other risk factors and potential confounders can be collected to increase the value of this type of non-interventional research for understanding the teratogenic effects of medications and other exposures during pregnancy. In summary, direct to consumer studies offer important benefits in obtaining data not found in prescription drug registers and electronic health records, and these type of studies will be most informative when combined with selected data from other sources to validate clinical outcomes of interest, and to corroborate most important exposures. 3 Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium Table of Contents List of tables ...................................................................................................................................................................... 8 List of figures ................................................................................................................................................................... 11 1 Introduction ............................................................................................................................................................ 13 1.1 Introduction