1. FROM “THE” PATIENT TO PRE-EMPT: A JOURNEY FROM THE INDIVIDUAL TO GLOBAL HEALTH Peter von Dadelszen BMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG Professor and Academic Head of Obstetrics & Gynaecology, SGUL Honorary Consultant in Obstetrics, SGFT 44 th APOG Meeting, 4 December 2015

2. Disclosures I have been a paid consultant to Alere International and have received unrestricted grants-in-aid from them to support some of the research presented I own shares in LGT Medical

3. Objectives Describe the important milestones in my journey as a clinician-scientist Primarily related to pre-eclampsia

4. Milestones Look at the big picture v1.1

5. Pre-eclampsia more than hypertension and proteinuria pre-eclampsia pulmonary oedema DIC/abruption hypertension stroke eclampsia proteinuria acute renal failure

6. Pre-eclampsia global burden Pre-eclampsia and the other HDP cause – IHME states 30,000 maternal deaths annually Kassebaum et al. Lancet 2014 – However, field data from Pakistan imply that 40% of 40,000 PPH deaths are attributable to pre-eclampsia upon review – Therefore, ≈46,000 maternal deaths annually At least one woman every 7 minutes – >500,000 perinatal deaths annually – ≈1500 deaths/d = 4 x A340s crashing daily However, no word for “pre-eclampsia” in Sindhi, Yoruba, Changana, Kannada … >99% of pre-eclampsia-related deaths occur in LMICs – Delays in triage, transport & treatment ≈50% of pre-eclampsia-related deaths occur in the home

7. Pre-eclampsia more than hypertension and proteinuria pre-eclampsia pulmonary oedema DIC/abruption hypertension stroke eclampsia proteinuria acute renal failure

8. Pre-eclampsia as PPH

9. Pre-eclampsia global burden Pre-eclampsia and the other HDP cause – IHME states 30,000 maternal deaths annually Kassebaum et al. Lancet 2014 – However, field data from Pakistan imply that 40% of 40,000 PPH deaths are attributable to pre-eclampsia upon review – Therefore, ≈46,000 maternal deaths annually At least one woman every 7 minutes – >500,000 perinatal deaths annually – ≈1500 deaths/d = 4 x A340s crashing daily However, no word for “pre-eclampsia” in Sindhi, Yoruba, Changana, Kannada … >99% of pre-eclampsia-related deaths occur in LMICs – Delays in triage, transport & treatment ≈50% of pre-eclampsia-related deaths occur in the home

10. Population-level incidence of HDP CLIP Trials Mozambique:Delivered women with hypertension: 70/964 (7.3%) Delivered women with proteinuric hypertension: 8/964 (0.8%)

11. GA at HDP recognition CLIP Trials

12. Mozambique: Completed pregnancies reporting severe hypertension: 20/964 (2.1%)

13. Milestones Look at the big picture v1.1 Look at the big picture v1.2

14. Data from CEMD,UK Maternal death from pre-eclampsia by diagnosis – UK; 1952 – 2008 Number of maternal deaths/triennium

15. Data from CEMD,UK Maternal death from pre-eclampsia by diagnosis – UK; 1952 – 2008 Number of maternal deaths/triennium AntihypertensivesMagnesium

16. Data from CEMD,UK Maternal death from pre-eclampsia by diagnosis – UK; 1952 – 2008 Number of maternal deaths/triennium AntihypertensivesMagnesium Surveillance, Timed delivery & Reproductive choice

17. Milestones Look at the big picture v1.1 Look at the big picture v1.2 Look at the big picture v1.3

18. cardiorespiratory hypertension ARDS pulmonary oedema cardiomyopathy / LV dysfunction intravascular volume constriction generalised oedema CNS eclampsia TIA / RIND / CVA PRES renal glomerular endotheliosis proteinuria ATN ARF hepatic periportal inflammation hepatic dysfunction / failure hepatic haematoma / rupture haematological microangiopathic haemolysis thrombocytopoenia DIC placental IUGR (± maternal syndrome) endothelial cell activation intervillous soup pre-eclampsia-specificshared with IUGR placental debris angiogenic imbalance innate immune activation oxidative stress eicosanoids cytokines uteroplacental mismatch decidual immune cell - EVT interactions (invasion & uteroplacental artery remodelling) inadequate placentation (early-onset pre-eclampsia) genetic factors familial risks SNPs epigenetics lowered threshold metabolic syndrome chronic infection / inflammation pre-existing hypertension chronic renal disease / DbM high altitude maternal syndrome normal placentation (late-onset pre-eclampsia) macrosomia multiple pregnancy ± lowered threshold immunological factors antigen exposure primigravidity ( ) / primipaternity ( ) donor gamete(s) ( ) duration of cohabitation ( ) barrier contraception ( ) / fellatio ( ) prior miscarriage ( ) smoking ( )

19. Milestones Look at the big picture v1.1 Look at the big picture v1.2 Look at the big picture v1.3 Your research is only as good as your controls

24. P L GF and IUGR vs constitutionally-small Preliminary data – Single site pilot study – Placental pathology to define placental IUGR Benton et al. AJOG 2011

25. P L GF and IUGR vs constutionally-small Constitutionally-small Placental IUGR Benton et al. submitted

26. STRIDER consortium of RCTs sildenafil 25mg tid NZ & Aus HRC (NZ) Netherlands (ZonMW) UK (MRC) ROI (HRB) Canada (CIHR)

27. cardiorespiratory hypertension ARDS pulmonary oedema cardiomyopathy / LV dysfunction intravascular volume constriction generalised oedema CNS eclampsia TIA / RIND / CVA PRES renal glomerular endotheliosis proteinuria ATN ARF hepatic periportal inflammation hepatic dysfunction / failure hepatic haematoma / rupture haematological microangiopathic haemolysis thrombocytopoenia DIC placental IUGR (± maternal syndrome) endothelial cell activation intervillous soup pre-eclampsia-specificshared with IUGR placental debris angiogenic imbalance innate immune activation oxidative stress eicosanoids cytokines uteroplacental mismatch decidual immune cell - EVT interactions (invasion & uteroplacental artery remodelling) inadequate placentation (early-onset pre-eclampsia) genetic factors familial risks SNPs epigenetics lowered threshold metabolic syndrome chronic infection / inflammation pre-existing hypertension chronic renal disease / DbM high altitude maternal syndrome normal placentation (late-onset pre-eclampsia) macrosomia multiple pregnancy ± lowered threshold immunological factors antigen exposure primigravidity ( ) / primipaternity ( ) donor gamete(s) ( ) duration of cohabitation ( ) barrier contraception ( ) / fellatio ( ) prior miscarriage ( ) smoking ( )

28. Milestones Look at the big picture v1.1 Look at the big picture v1.2 Look at the big picture v1.3 Your research is only as good as your controls Tell a story

29. cardiorespiratory hypertension ARDS pulmonary oedema cardiomyopathy / LV dysfunction intravascular volume constriction generalised oedema CNS eclampsia TIA / RIND / CVA PRES renal glomerular endotheliosis proteinuria ATN ARF hepatic periportal inflammation hepatic dysfunction / failure hepatic haematoma / rupture haematological microangiopathic haemolysis thrombocytopoenia DIC placental IUGR (± maternal syndrome) endothelial cell activation intervillous soup pre-eclampsia-specificshared with IUGR placental debris angiogenic imbalance innate immune activation oxidative stress eicosanoids cytokines uteroplacental mismatch decidual immune cell - EVT interactions (invasion & uteroplacental artery remodelling) inadequate placentation (early-onset pre-eclampsia) genetic factors familial risks SNPs epigenetics lowered threshold metabolic syndrome chronic infection / inflammation pre-existing hypertension chronic renal disease / DbM high altitude maternal syndrome normal placentation (late-onset pre-eclampsia) macrosomia multiple pregnancy ± lowered threshold immunological factors antigen exposure primigravidity ( ) / primipaternity ( ) donor gamete(s) ( ) duration of cohabitation ( ) barrier contraception ( ) / fellatio ( ) prior miscarriage ( ) smoking ( )

34. fullPIERS sites 2023 women von Dadelszen et al. Lancet 2011

38. Payne et al. PLoS Med 2014

39. home-based (± transfer to PHC) or PHC-based assessment & initial management App-guided CLIP package of care (≥1 trigger) 750mg methyldopa po (only if sBP ≥160; not repeated in PHC) 10g MgSO 4 im (if sBP ≥160, eclampsia, miniPIERS p ≥25%, pv bleeding + sBP≥140; not repeated in PHC) urgent transport (if sBP ≥160, eclampsia, coma, stroke, miniPIERS p ≥25%, pv bleeding, ++++ protein, no FM ≥12h) App-guided CLIP triggers to OVERCOMING initiate community interventions THE 3 DELAYS miniPIERS p ≥25% Triage/Transport/Treatment sBP ≥160Triage/Transport/Treatment eclampsiaTriage/Transport/Treatment pv bleeding (presumed abruption)Triage/Transport/Treatment ++++ proteinuriaTriage/Transport/Treatment absent fetal movements ≥12hTriage/Transport/Treatment community engagement & cHCP education urgent transport (<4h) (if: miniPIERS p ≥25%, sBP ≥160, stroke, coma, eclampsia, pv bleeding, ++++ protein, absent FM ≥12h) non-urgent transport (<24h) (if: miniPIERS p <25%, sBP 140-159mmHg, <++++ protein) facility capacity enhancement CME/CPD M&M reviews CEmOC facility for definitive care ongoing BP control ongoing MgSO 4 delivery – IOL vs C/S newborn care

40. community engagement & cHCP education urgent transport (<4h) (if: miniPIERS p ≥25%, sBP ≥160, stroke, coma, eclampsia, pv bleeding, ++++ protein, absent FM ≥12h) non-urgent transport (<24h) (if: miniPIERS p <25%, sBP 140-159mmHg, <++++ protein) facility capacity enhancement CME/CPD M&M reviews home-based (± transfer to PHC) or PHC-based assessment & initial management App-guided CLIP package of care (≥1 trigger) 750mg methyldopa po (only if sBP ≥160, dBP ≥110; not repeated in PHC) 10g MgSO 4 im (if sBP ≥160, dBP ≥110, eclampsia, miniPIERS p ≥25%, pv bleeding + sBP≥140; not repeated in PHC) urgent transport (if sBP ≥160, dBP ≥110, SI ≥1.7, eclampsia, coma, stroke, miniPIERS p ≥25%, pv bleeding, ++++ protein, no FM ≥12h) App-guided CLIP triggers to OVERCOMING initiate community interventions THE 3 DELAYS miniPIERS p ≥25% Triage/Transport/Treatment sBP ≥160Triage/Transport/Treatment dBP ≥110Triage/Transport/Treatment SI ≥1.7Triage/Transport/Treatment eclampsiaTriage/Transport/Treatment pv bleeding (presumed abruption)Triage/Transport/Treatment ++++ proteinuriaTriage/Transport/Treatment absent fetal movements ≥12hTriage/Transport/Treatment CEmOC facility for definitive care ongoing BP control ongoing MgSO 4 delivery – IOL vs C/S newborn care

41. Payne et al. JOGC 2015

42. additional 20% of women who will suffer adverse outcome identified increased from 65% to 85% additional 20% of women who will suffer adverse outcome identified increased from 65% to 85% Payne et al. JOGC 2015

44. community engagement & cHCP education urgent transport (<4h) (if: miniPIERS p ≥25%, sBP ≥160, stroke, coma, eclampsia, pv bleeding, ++++ protein, absent FM ≥12h) non-urgent transport (<24h) (if: miniPIERS p <25%, sBP 140-159mmHg, <++++ protein) facility capacity enhancement CME/CPD M&M reviews home-based (± transfer to PHC) or PHC-based assessment & initial management App-guided CLIP package of care (≥1 trigger) 750mg methyldopa po (if sBP ≥160; not repeated in PHC) 10g MgSO 4 im(if sBP ≥160, eclampsia, miniPIERS p ≥25%, pv bleeding + sBP≥140; not repeated in PHC) urgent transport (if sBP ≥160, SpO 2 <93%, eclampsia, coma, stroke, miniPIERS p ≥25%, pv bleeding, ++++ protein, no FM ≥12h) App-guided CLIP triggers to OVERCOMING initiate community interventions THE 3 DELAYS miniPIERS p ≥25% Triage/Transport/Treatment sBP ≥160Triage/Transport/Treatment SpO 2 <93% Triage/Transport/Treatment eclampsiaTriage/Transport/Treatment pv bleeding (presumed abruption)Triage/Transport/Treatment ++++ proteinuriaTriage/Transport/Treatment absent fetal movements ≥12hTriage/Transport/Treatment CEmOC facility for definitive care ongoing BP control ongoing MgSO 4 delivery – IOL vs C/S newborn care

45. cardiorespiratory hypertension ARDS pulmonary oedema cardiomyopathy / LV dysfunction intravascular volume constriction generalised oedema CNS eclampsia TIA / RIND / CVA PRES renal glomerular endotheliosis proteinuria ATN ARF hepatic periportal inflammation hepatic dysfunction / failure hepatic haematoma / rupture haematological microangiopathic haemolysis thrombocytopoenia DIC placental IUGR (± maternal syndrome) endothelial cell activation intervillous soup pre-eclampsia-specificshared with IUGR placental debris angiogenic imbalance innate immune activation oxidative stress eicosanoids cytokines uteroplacental mismatch decidual immune cell - EVT interactions (invasion & uteroplacental artery remodelling) inadequate placentation (early-onset pre-eclampsia) genetic factors familial risks SNPs epigenetics lowered threshold metabolic syndrome chronic infection / inflammation pre-existing hypertension chronic renal disease / DbM high altitude maternal syndrome normal placentation (late-onset pre-eclampsia) macrosomia multiple pregnancy ± lowered threshold immunological factors antigen exposure primigravidity ( ) / primipaternity ( ) donor gamete(s) ( ) duration of cohabitation ( ) barrier contraception ( ) / fellatio ( ) prior miscarriage ( ) smoking ( )

46. Milestones Look at the big picture v1.1 Look at the big picture v1.2 Look at the big picture v1.3 Your research is only as good as your controls Tell a story And finally …

47. Marry well!