Transcript New insights into the placental complications of pregnancy

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
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-eclampsia
more than hypertension and proteinuria
hypertension
proteinuria
pre-eclampsia
pulmonary oedema
acute renal failure
eclampsia
stroke
DIC/abruption
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
Pre-eclampsia
more than hypertension and proteinuria
hypertension
proteinuria
pre-eclampsia
pulmonary oedema
acute renal failure
eclampsia
stroke
DIC/abruption
Pre-eclampsia as PPH
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
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%)
GA at HDP recognition
CLIP Trials
GA at HDP recognition
CLIP 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
Maternal death from pre-eclampsia
Number of maternal deaths/triennium
by diagnosis – UK; 1952 – 2008
Data from CEMD ,UK
Maternal death from pre-eclampsia
by diagnosis – UK; 1952 – 2008
Magnesium
Number of maternal deaths/triennium
Antihypertensives
Data from CEMD ,UK
Maternal death from pre-eclampsia
by diagnosis – UK; 1952 – 2008
Antihypertensives
Magnesium
Number of maternal deaths/triennium
Surveillance,
Timed delivery &
Reproductive choice
Data from CEMD ,UK
Milestones
• Look at the big picture v1.1
• Look at the big picture v1.2
• Look at the big picture v1.3
immunological factors
decidual immune cell EVT interactions
antigen exposure
• primigravidity ( ) / primipaternity ( )
• donor gamete(s) ( )
• duration of cohabitation ( )
• barrier contraception ( ) / fellatio ( )
• prior miscarriage ( )
• smoking ( )
(invasion & uteroplacental
artery remodelling)
normal placentation
(late-onset pre-eclampsia)
•macrosomia
•multiple pregnancy
•± lowered threshold
inadequate placentation
(early-onset pre-eclampsia)
genetic factors
• familial risks
• SNPs
• epigenetics
uteroplacental mismatch
placental IUGR
intervillous soup
lowered threshold
pre-eclampsia-specific
•placental debris
•innate immune activation
•oxidative stress
•eicosanoids
•cytokines
• metabolic syndrome
• chronic infection / inflammation
• pre-existing hypertension
• chronic renal disease / DbM
• high altitude
(± maternal syndrome)
shared with IUGR
•angiogenic imbalance
endothelial cell activation
cardiorespiratory
CNS
renal
hepatic
haematological
•hypertension
•ARDS
•pulmonary oedema
•cardiomyopathy / LV dysfunction
•intravascular volume constriction
•generalised oedema
•eclampsia
•TIA / RIND / CVA
•PRES
•glomerular endotheliosis
•proteinuria
•ATN
•ARF
•periportal inflammation
•hepatic dysfunction / failure
•hepatic haematoma / rupture
•microangiopathic haemolysis
•thrombocytopoenia
•DIC
maternal syndrome
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
Placental growth factor (pg/mL)
10000
Grade 0
Grade 1
Grade 2
Grade 3
Constitutionally-small
Placental IUGR
1000
100
10
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Gestational age at sampling (week)
Benton et al. submitted
STRIDER consortium of RCTs
sildenafil 25mg tid
UK
(MRC)
Canada
(CIHR)
ROI
(HRB)
Netherlands
(ZonMW)
NZ & Aus
HRC (NZ)
STRIDER
immunological factors
decidual immune cell EVT interactions
antigen exposure
• primigravidity ( ) / primipaternity ( )
• donor gamete(s) ( )
• duration of cohabitation ( )
• barrier contraception ( ) / fellatio ( )
• prior miscarriage ( )
• smoking ( )
(invasion & uteroplacental
artery remodelling)
normal placentation
(late-onset pre-eclampsia)
•macrosomia
•multiple pregnancy
•± lowered threshold
inadequate placentation
(early-onset pre-eclampsia)
genetic factors
• familial risks
• SNPs
• epigenetics
uteroplacental mismatch
placental IUGR
intervillous soup
lowered threshold
pre-eclampsia-specific
•placental debris
•innate immune activation
•oxidative stress
•eicosanoids
•cytokines
• metabolic syndrome
• chronic infection / inflammation
• pre-existing hypertension
• chronic renal disease / DbM
• high altitude
(± maternal syndrome)
shared with IUGR
•angiogenic imbalance
endothelial cell activation
cardiorespiratory
CNS
renal
hepatic
haematological
•hypertension
•ARDS
•pulmonary oedema
•cardiomyopathy / LV dysfunction
•intravascular volume constriction
•generalised oedema
•eclampsia
•TIA / RIND / CVA
•PRES
•glomerular endotheliosis
•proteinuria
•ATN
•ARF
•periportal inflammation
•hepatic dysfunction / failure
•hepatic haematoma / rupture
•microangiopathic haemolysis
•thrombocytopoenia
•DIC
maternal syndrome
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
immunological factors
decidual immune cell EVT interactions
antigen exposure
• primigravidity ( ) / primipaternity ( )
• donor gamete(s) ( )
• duration of cohabitation ( )
• barrier contraception ( ) / fellatio ( )
• prior miscarriage ( )
• smoking ( )
(invasion & uteroplacental
artery remodelling)
normal placentation
(late-onset pre-eclampsia)
•macrosomia
•multiple pregnancy
•± lowered threshold
inadequate placentation
(early-onset pre-eclampsia)
genetic factors
• familial risks
• SNPs
• epigenetics
uteroplacental mismatch
placental IUGR
intervillous soup
lowered threshold
pre-eclampsia-specific
•placental debris
•innate immune activation
•oxidative stress
•eicosanoids
•cytokines
• metabolic syndrome
• chronic infection / inflammation
• pre-existing hypertension
• chronic renal disease / DbM
• high altitude
(± maternal syndrome)
shared with IUGR
•angiogenic imbalance
endothelial cell activation
cardiorespiratory
CNS
renal
hepatic
haematological
•hypertension
•ARDS
•pulmonary oedema
•cardiomyopathy / LV dysfunction
•intravascular volume constriction
•generalised oedema
•eclampsia
•TIA / RIND / CVA
•PRES
•glomerular endotheliosis
•proteinuria
•ATN
•ARF
•periportal inflammation
•hepatic dysfunction / failure
•hepatic haematoma / rupture
•microangiopathic haemolysis
•thrombocytopoenia
•DIC
maternal syndrome
fullPIERS sites
2023 women
Vancouver
Richmond
Surrey
Cranbrook
Kingston
Ottawa
Sherbrooke
Leeds
Nottingham
Perth
Christchurch
von Dadelszen et al. Lancet 2011
Payne et al. PLoS Med 2014
App-guided CLIP triggers to
initiate community interventions
miniPIERS p ≥25%
sBP ≥160
eclampsia
pv bleeding (presumed abruption)
++++ proteinuria
absent fetal movements ≥12h
OVERCOMING
THE 3 DELAYS
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
facility capacity
enhancement
CME/CPD
M&M reviews
urgent transport (<4h)
community
engagement
& cHCP
education
home-based
(± transfer to PHC)
or PHC-based
assessment &
initial
management
(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)
CEmOC facility for
definitive care
ongoing BP control
ongoing MgSO4
delivery – IOL vs C/S
newborn care
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
initiate community interventions
miniPIERS p ≥25%
sBP ≥160
dBP ≥110
SI ≥1.7
eclampsia
pv bleeding (presumed abruption)
++++ proteinuria
absent fetal movements ≥12h
OVERCOMING
THE 3 DELAYS
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
facility capacity
enhancement
CME/CPD
M&M reviews
urgent transport (<4h)
community
engagement
& cHCP
education
home-based
(± transfer to PHC)
or PHC-based
assessment &
initial
management
(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)
CEmOC facility for
definitive care
ongoing BP control
ongoing MgSO4
delivery – IOL vs C/S
newborn care
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)
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
App-guided CLIP triggers to
initiate community interventions
miniPIERS p ≥25%
sBP ≥160
SpO2 <93%
eclampsia
pv bleeding (presumed abruption)
++++ proteinuria
absent fetal movements ≥12h
OVERCOMING
THE 3 DELAYS
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
Triage/Transport/Treatment
facility capacity
enhancement
CME/CPD
M&M reviews
urgent transport (<4h)
community
engagement
& cHCP
education
home-based
(± transfer to PHC)
or PHC-based
assessment &
initial
management
(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)
CEmOC facility for
definitive care
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)
ongoing BP control
ongoing MgSO4
delivery – IOL vs C/S
newborn care
immunological factors
decidual immune cell EVT interactions
antigen exposure
• primigravidity ( ) / primipaternity ( )
• donor gamete(s) ( )
• duration of cohabitation ( )
• barrier contraception ( ) / fellatio ( )
• prior miscarriage ( )
• smoking ( )
(invasion & uteroplacental
artery remodelling)
normal placentation
(late-onset pre-eclampsia)
•macrosomia
•multiple pregnancy
•± lowered threshold
inadequate placentation
(early-onset pre-eclampsia)
genetic factors
• familial risks
• SNPs
• epigenetics
uteroplacental mismatch
placental IUGR
intervillous soup
lowered threshold
pre-eclampsia-specific
•placental debris
•innate immune activation
•oxidative stress
•eicosanoids
•cytokines
• metabolic syndrome
• chronic infection / inflammation
• pre-existing hypertension
• chronic renal disease / DbM
• high altitude
(± maternal syndrome)
shared with IUGR
•angiogenic imbalance
endothelial cell activation
cardiorespiratory
CNS
renal
hepatic
haematological
•hypertension
•ARDS
•pulmonary oedema
•cardiomyopathy / LV dysfunction
•intravascular volume constriction
•generalised oedema
•eclampsia
•TIA / RIND / CVA
•PRES
•glomerular endotheliosis
•proteinuria
•ATN
•ARF
•periportal inflammation
•hepatic dysfunction / failure
•hepatic haematoma / rupture
•microangiopathic haemolysis
•thrombocytopoenia
•DIC
maternal syndrome
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!