from “the” patient to pre-empt: a journey from the individual to global health peter von...

FROM “THE” PATIENT TO PRE-EMPT: A JOURNEY FROM THE INDIVIDUAL TO

GLOBAL HEALTH

Peter von DadelszenBMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG

Professor and Academic Head of Obstetrics & Gynaecology, SGULHonorary Consultant in Obstetrics, SGFT

44th APOG Meeting, 4 December 2015

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

Objectives

• Describe the important milestones in my journey as a clinician-scientist

• Primarily related to pre-eclampsia

Milestones

• Look at the big picture v1.1

Pre-eclampsiamore than hypertension and proteinuria

pre-eclampsia

pulmonary oedema

DIC/abruption

hypertension

strokeeclampsia

proteinuria

acute renal failure

Pre-eclampsiaglobal 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

Pre-eclampsiamore than hypertension and proteinuria

pre-eclampsia

pulmonary oedema

DIC/abruption

hypertension

strokeeclampsia

proteinuria

acute renal failure

Pre-eclampsia as PPH

Pre-eclampsiaglobal 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

Population-level incidence of HDPCLIP Trials

Mozambique: Delivered women with hypertension: 70/964 (7.3%) Delivered women with proteinuric hypertension: 8/964 (0.8%)

GA at HDP recognitionCLIP Trials

GA at HDP recognitionCLIP Trials

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

Milestones

• Look at the big picture v1.1• Look at the big picture v1.2

Data from CEMD ,UK

Maternal death from pre-eclampsiaby diagnosis – UK; 1952 – 2008

Num

ber o

f mat

erna

l dea

ths/

trie

nniu

m

Data from CEMD ,UK

Maternal death from pre-eclampsiaby diagnosis – UK; 1952 – 2008

Num

ber o

f mat

erna

l dea

ths/

trie

nniu

m

Antihypertensives Magnesium

Data from CEMD ,UK

Maternal death from pre-eclampsiaby diagnosis – UK; 1952 – 2008

Num

ber o

f mat

erna

l dea

ths/

trie

nniu

m

Antihypertensives Magnesium

Surveillance,Timed delivery &

Reproductive choice

Milestones

• Look at the big picture v1.1• Look at the big picture v1.2• Look at the big picture v1.3

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 souppre-eclampsia-specific shared 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 factorsantigen exposure• primigravidity ( ) / primipaternity ( )• donor gamete(s) ( )• duration of cohabitation ( )• barrier contraception ( ) / fellatio ( )• prior miscarriage ( )• smoking ( )

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

PLGF and IUGR vs constitutionally-small

• Preliminary data– Single site pilot study– Placental pathology to define placental IUGR

Benton et al. AJOG 2011

PLGF and IUGR vs constutionally-small

Gestational age at sampling (week)

Pla

ce

nta

l gro

wth

fa

cto

r (p

g/m

L)

20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 4010

100

1000

10000 Grade 0Grade 1Grade 2Grade 3

Constitutionally-small

Placental IUGR

Benton et al. submitted

STRIDER consortium of RCTssildenafil 25mg tid

NZ & AusHRC (NZ)

Netherlands(ZonMW)

UK(MRC)

ROI(HRB)

Canada(CIHR)

STRIDER

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 souppre-eclampsia-specific shared 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 factorsantigen exposure• primigravidity ( ) / primipaternity ( )• donor gamete(s) ( )• duration of cohabitation ( )• barrier contraception ( ) / fellatio ( )• prior miscarriage ( )• smoking ( )

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

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 souppre-eclampsia-specific shared 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 factorsantigen exposure• primigravidity ( ) / primipaternity ( )• donor gamete(s) ( )• duration of cohabitation ( )• barrier contraception ( ) / fellatio ( )• prior miscarriage ( )• smoking ( )

fullPIERS sites2023 women

Christchurch

Perth

Nottingham

LeedsKingstonOttawa

Sherbrooke

VancouverRichmond

SurreyCranbrook

von Dadelszen et al. Lancet 2011

Payne et al. PLoS Med 2014

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 MgSO4 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 OVERCOMINGinitiate community interventions THE 3 DELAYSminiPIERS p ≥25% Triage/Transport/TreatmentsBP ≥160 Triage/Transport/Treatmenteclampsia Triage/Transport/Treatmentpv bleeding (presumed abruption) Triage/Transport/Treatment++++ proteinuria Triage/Transport/Treatmentabsent fetal movements ≥12h Triage/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/CPDM&M reviews

CEmOC facility for definitive care

ongoing BP controlongoing MgSO4

delivery – IOL vs C/Snewborn care

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/CPDM&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 MgSO4 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 OVERCOMINGinitiate community interventions THE 3 DELAYSminiPIERS p ≥25% Triage/Transport/TreatmentsBP ≥160 Triage/Transport/TreatmentdBP ≥110 Triage/Transport/TreatmentSI ≥1.7 Triage/Transport/Treatmenteclampsia Triage/Transport/Treatmentpv bleeding (presumed abruption) Triage/Transport/Treatment++++ proteinuria Triage/Transport/Treatmentabsent fetal movements ≥12h Triage/Transport/Treatment

CEmOC facility for definitive care

ongoing BP controlongoing MgSO4

delivery – IOL vs C/Snewborn care

Payne et al. JOGC 2015

• additional 20% of women who will suffer adverse outcome identified• increased from 65% to 85%

Payne et al. JOGC 2015

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/CPDM&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 MgSO4 im (if sBP ≥160, eclampsia, miniPIERS p ≥25%, pv bleeding + sBP≥140; not repeated in PHC)urgent transport (if sBP ≥160, SpO2 <93%, eclampsia, coma, stroke, miniPIERS p ≥25%, pv bleeding, ++++ protein, no FM ≥12h)

App-guided CLIP triggers to OVERCOMINGinitiate community interventions THE 3 DELAYSminiPIERS p ≥25% Triage/Transport/TreatmentsBP ≥160 Triage/Transport/TreatmentSpO2 <93% Triage/Transport/Treatmenteclampsia Triage/Transport/Treatmentpv bleeding (presumed abruption) Triage/Transport/Treatment++++ proteinuria Triage/Transport/Treatmentabsent fetal movements ≥12h Triage/Transport/Treatment

CEmOC facility for definitive care

ongoing BP controlongoing MgSO4

delivery – IOL vs C/Snewborn care

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 souppre-eclampsia-specific shared 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 factorsantigen exposure• primigravidity ( ) / primipaternity ( )• donor gamete(s) ( )• duration of cohabitation ( )• barrier contraception ( ) / fellatio ( )• prior miscarriage ( )• smoking ( )

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 …

Marry well!