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Report of the Commission on Human Medicines Expert Working Group on Hormone Pregnancy Tests Contents

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Report of the Commission on Human Medicines Expert Working Group on Hormone Pregnancy Tests Contents REPORTREPORT OF OF THE THE COMMISSIONCOMMISSION ON ON HUMANHUMAN MEDICINES MEDICINES EXPERT WORKING GROUP ON EXPERTHORMON WORKINGE PREGNANCY GROUP TEST ONS HORMONE PREGNANCY TESTS October 2017 October 2017 i REPORT OF THE COMMISSION ON HUMAN MEDICINES EXPERT WORKING GROUP ON HORMONE PREGNANCY TESTS CONTENTS Foreword……………………………………………………………..…………………………………...…………………………v Lay summary…………………………………………………………..…………………………………………….…..……….vii Abbreviations…………………………………………………………………………………………………………………….xxii 1 INTRODUCTION ................................................................................................ 1 1.1 Background to the review ....................................................................................................... 1 1.1.1 Concern with HPTs .......................................................................................................... 1 1.1.2 The need for a scientific review ...................................................................................... 1 1.2 The Expert Working Group on HPTs ........................................................................................ 2 1.2.1 Remit of the Expert Working Group on HPTs ................................................................. 2 1.2.2 Scope of the review ........................................................................................................ 3 1.2.3 Programme of work ........................................................................................................ 3 1.2.4 Key data sources ............................................................................................................. 4 1.2.5 Terminology .................................................................................................................... 7 1.3 Membership of the Expert Working Group .................................................................... 8 1.3.1 Conflicts of interest ................................................................................................................. 8 1.3.2 Membership ........................................................................................................................... 9 2 HISTORICAL AND SCIENTIFIC CONTEXT ............................................................ 12 2.1 Historical perspective ............................................................................................................ 12 2.1.1 Socio-medical environment .......................................................................................... 12 2.1.2 Early medicines regulation ............................................................................................ 13 2.2 Scientific context ................................................................................................................... 14 2.2.1 Hormonal steroids......................................................................................................... 14 2.2.2 Role of sex hormones in the mother and fetus ............................................................ 14 2.2.3 Congenital anomalies and their natural occurrence ..................................................... 14 2.3 Hormone Pregnancy Tests in the UK ..................................................................................... 15 2.3.1 Synthetic sex hormones ................................................................................................ 15 2.3.2 HPT products ................................................................................................................. 15 2.3.3 Usage of HPTs in the UK ................................................................................................ 17 2.4 Key UK regulatory action taken on HPTs ............................................................................... 19 3 INTRODUCTION TO PHARMACOVIGILANCE AND STRENGTH OF TYPES OF EVIDENCE ....................................................................................................... 21 3.1 Pharmacovigilance ................................................................................................................. 21 3.2 Sources of evidence – the importance and impact of study design ..................................... 21 3.2.1 Randomised controlled trials ........................................................................................ 22 3.2.2 Observational studies ................................................................................................... 22 3.2.3 Reports of suspected adverse reactions (spontaneous reporting data) ...................... 23 3.2.4 Animal research ............................................................................................................ 23 3.2.5 In vitro or laboratory based research ........................................................................... 23 3.2.6 Ideas, editorials, anecdotes, letters and opinions ........................................................ 24 3.3 Strength of the evidence in this review ................................................................................. 24 3.3.1 General considerations ................................................................................................. 24 3.3.2 Epidemiological data ..................................................................................................... 24 3.3.3 Adverse event reporting data ....................................................................................... 25 ii 3.3.4 Animal data ................................................................................................................... 25 3.3.5 Overall conclusion ......................................................................................................... 26 4 PHARMACOLOGICAL CONSIDERATIONS RELATING TO EFFECTS OF HORMONE PREGNANCY TESTS ON THE DEVELOPING FETUS ............................................. 27 4.1 Timing of administration of HPTs .......................................................................................... 27 4.2 Crossing the placental barrier ............................................................................................... 28 4.2.1 Maternal absorption of Primodos ................................................................................. 28 4.2.2 Transfer of norethisterone and ethinylestradiol across the placenta .......................... 31 4.3 Receptor expression during fetal development .................................................................... 32 4.4 Placental and fetal activity of ethinylestradiol and norethisterone ...................................... 33 4.4.1 Norethisterone .............................................................................................................. 33 4.4.1 Ethinylestradiol ............................................................................................................. 33 4.5 Limitations of the evidence ................................................................................................... 34 4.6 Discussion of the pharmacological data ................................................................................ 34 4.7 Key observations ................................................................................................................... 35 4.8 Overall conclusion on pharmacological considerations ........................................................ 35 5 EXPOSURE TO HORMONE PREGNANCY TESTS IN PREGNANCY AND EVIDENCE RELATING TO POSSIBLE ASSOCIATION WITH CONGENITAL ANOMALIES .......... 36 5.1 Mechanistic evidence ............................................................................................................ 36 5.1.1 General toxicity ............................................................................................................. 36 5.1.2 Genotoxicity .................................................................................................................. 36 5.1.3 Reproductive toxicity .................................................................................................... 37 5.1.4 Vascular disruption with norethisterone and ethinylestradiol ..................................... 46 5.1.5 Overall conclusion on vascular disruption .................................................................... 49 5.2 Reports of suspected adverse drug reactions ....................................................................... 49 5.2.1 Information obtained .................................................................................................... 49 5.2.2 Handling of duplicate reports ....................................................................................... 50 5.2.3 Re-categorisation of cases ............................................................................................ 52 5.2.4 Comparison of reporting with the Yellow Card database ............................................. 56 5.2.5 Discussion of adverse event data.................................................................................. 56 5.2.6 Key observations ........................................................................................................... 58 5.2.7 Overall conclusion on adverse event data .................................................................... 58 5.3 Epidemiological evidence ...................................................................................................... 58 5.3.1 Data obtained ..............................................................................................................
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