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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