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19 October 2005
Preeclampsia: challenging the placental origins hypothesis
NIPT
Current knowledge
UtA Doppler and Endovascular Trophoblast Invasion
The Fetal Medicine Foundation
0
20
40
60
80
100
Normal PE
PlGF
Early screening for PE
Ovulation drugs
History of hypertension
Maternal history of PE
Previous PE
No previous PE
Parous
Mixed
Indian or Pakistani
Black
Racial origin
BMI (Kg/m2)
Maternal age (yr)
History
6% Screen +ve
Early-PE 40/50
Late-PE 90/200
10,000 pregnancies
600 pregnancies
50% detection
“Maternal” Preeclampsia
80% of PE occurs at term with features that are inconsistent with the placental origins hypothesis
‘Maternal’ PE or ‘heterogeniety’ are
neither adequate nor actual explanations
Effect
Placenta Required
Fetal growth Compromised
Cured by Birth
Maternal organ system Compromised
Postpartum Legacy effect
Aetiology of preeclampsia
Disorder ONLY occurs in pregnancy
gestational diabetes
Placental Histology
Numerous classic placental histological villous and vascular lesions described
• Villous infarcts • Villitis • Villous hypoplasia • Syncytial knots • Vasculopathy • Muscularisation • Acute atherosis
Association or Causation?
Placental Histology Villous lesions 6-times more
prevalent in preeclampsia
Falco M et al. UOG. (in press)
In a hypothetical cohort of 1000 women
50 women with preeclampsia
60% with villous lesions (n=30)
10% of normal pregnancies have villous lesions (n=100)
Vascular ♯: Normal=10, PE=10
Placental Histology
Daskalakis G et al. Acta O&G 2008 Huynh J et al. Placenta 2015
Placental histology is neither sensitive nor
specific for preeclampsia
Fetal Growth Restriction in PE
Most cases of PE (80%) occur at term Most term PE cases (85%) are not SGA
Term PE is also associated with LGA births
Term PE - SGA form
Term PE - LGA form
Ultrasound Obstet Gynecol. 2014 Sep;44(3):293-8.
Norwegian registry 80,000 pregnancies
3000 with PE
Preeclampsia Epidemiology
Cardiovascular legacy
20-29yrs
40-49yrs
20-29yrs + PE
40-49yrs + PE
Ida Brehens et al. (in press)
1m Danish births linked to national prescription register
How does abdominal implantation of the
placenta explain low UtA PI due to spiral artery conversion?
Collins SL et al. Placenta 2011 Leslie K et al. Placenta 2012
Mahendru A et al. J Hypertens. 2014
Uterine Artery and Trophoblast Invasion
Ophthalmic Artery Doppler
1st trimester ophthalmic artery Doppler is associated with PE
Kalafat E et al. Ultrasound Obstet Gynecol. (in press)
Gestational diabetes
Cardiac hypertrophy
Increase in LV mass
Elite athletes (2yrs) - 25% Pregnancy (38wks) - 40%
ASE/ESE criteria to diagnose concentric hypertrophy of LV
Cardiac remodelling
Term pregnancy 25% trabeculations
Myocardial and ventricular function
010
2030
T1 T2 T3 Term PP
Prev
alen
ce %
Impaired relaxation Diastolic dysfunction
#
#
#
Melchiorre K et al. Hypertension 2016
Mean E’/A’ <1 ASE/EAE algorithm 8 of 9 were
NYHA class 4
Physiological Adaptation or Cardiac Dysfunction?
• Changes in cardiac indices consistent • Expected response to volume load • Magnitude of change unexpected: • Cardiac signs correlate to symptoms
www.heart-failure.co.uk
Cardiovascular maladaptation
Pregnancy
Preeclampsia
Cardiovascular dysfunction in preeclampsia
Melchiorre K et al. Circulation 2014:130:703-14
0
20
40
60
80
100
Impaired relaxation (%) Diastolic dysfunction (%)
Preterm PE Term PE Term PP/NPC
Cardiac Output
2
2.5
3
3.5
4
PretermPE
Term PE Term PP/NPC
CI (L/min/m2)
Cardiac Output versus insulin
Inadequate trophoblast invasion/development
Preterm Preeclampsia
Relative cardiac insufficiency (high fetoplacental demands)
Term Preeclampsia
Placental ‘stress’ response
Release of placental factors
Endothelial cell activation
Syndrome of preeclampsia
Dual cardiovascular AND placental aetiology of PE
Complex aetiology or unifying hypothesis?
Impaired placentation
Cardiovascular dysfunction
FGR PE (AGA/LGA) Mainly at term
PE (SGA-type) Mainly preterm
Preeclampsia: getting to the heart of the matter. Thilaganathan B, UOG, Jan 2017
Effect of parity • Weight gain greatest in 1st pregnancy
• Reduced fecundity after preterm PE
• Protective effect of pregnancy
McDonald-Wallis et al. AmJOG
Skjaerven R et al. BMJ 2012
Melchiorre K et al. Circulation 2014
Clapp JF et al. Am J Cardiol 1997
Multipara
Nullipara
19 October 2005
Basky Thilaganathan cfDNA: a case-based presentation
• False positive rate of 3%
• Detection rate of about 75%
Assessing Risk Combined NT and biochemistry
Wright D et al. Ultrasound Obstet Gynecol. 2010;36:404-11
Invasive prenatal tests
Cicero et al., 2001
Tabor A et al. Ultrasound Obstet Gynecol. 2009;34:19-24.
Fetal cells and cfDNA
Cicero et al., 2001
Fetal cfDNA • Originates from trophoblast
• Detectable from 5 weeks
• 5-10% of total cell-free DNA
• Cleared immediately after birth Lo YM et al. Am J Human Genetics. 1998;62:768-75
Maternal Plasma
DNA Extraction
Library Preparation Sequencing Analysis
10 mL blood sample is collected from the expectant mother.
Fully automated DNA extraction is carried out on the QIAsymphony®.
Library preparation using the NGS
Sciclone®. Sample quantitation is
done with LabChip® GX Touch.
Sample prepared for downstream sequencing using
the ION Chef™ and then analyzed on the ION Proton™
systems.
Automated data analysis with the IONA® Software.
3 Days
Principles of NIPT
Assume 10% of cfDNA is fetal
Need to distinguish 21 copies from 20 copies (5% difference)
Chromosome 18 Chromosome 21 (T21)
18m + 2f = 20 copies 18m + 3f = 21 copies
Meta-analysis of NIPT
Does the a-priori T21 risk matter when using NIPT?
Q1
Prior Risks Maternal age Gestational age Previous Trisomy
Test risk For T21, T18, T13
NT βhCG PAPP-A
Can we trust a very low-risk result in a 42yr old?
Q2
Takoudes T et al. UOG 2013
Apparent commercial justification for NOT measuring FF: • Unnecessary (0.5% x 1:700 = 1:140,000 risk of T21) • Costly (laboratory and bioinformatics) • Unreliable (various methods of FF estimation)
If we measure fetal fraction, the test fails more often
Q3
80% 3%
Results with fetal fraction of 4% and 12% are equally reliable
Q4
15%
FF Normal T21 Diff 12% 88+12 88+18 6% 4% 96+4 96+6 2%
How do we compromise between cfDNA failure rates
and test accuracy?
Q5
30
40
50
60
70
80
90
100
DR
(%)
FPR
(%)
0 1 2 3 4 5 6 7 8 >9 Fetal fraction (%)
0
1
2
3
4
5
6
7
Optimising test performance Use correct a-priori risk
Dynamic FF integrated into risk
30
40
50
60
70
80
90
100
DR
(%)
FPR
(%)
0 1 2 3 4 5 6 7 8 >9 Fetal fraction (%)
0
1
2
3
4
5
6
7
FF (%) MA + cf DNA CT + cf DNA MA + cf DNA CT + cf DNA 0.1% 37% 86% 6.0% 2.6% 1% 44% 87% 6.0% 2.5% 2% 62% 90% 6.0% 2.1% 3% 78% 94% 4.6% 1.5% 4% 88% 96% 2.8% 1.0% 5% 94% 98% 1.5% 0.5% 6% 97% 99% 0.7% 0.2% 7% >99% >99% 0.3% 0.1% 8% >99% >99% 0.1% <0.1% >9% >99% >99% <0.1% <0.1%
Detection Rate False Positive Rate
Are cfDNA test results easier for women to understand?
Q6
1:20,000
1:10,000
1:1000
1:100
1:10
1:1
Crown-rump length (mm)
45 50 55 60 65 70 75 80 85
Estim
ated
risk
for t
risom
y
1:20,000
1:10,000
1:1000
1:100
1:10
1:1
Crown-rump length (mm)
45 50 55 60 65 70 75 80 85
Estim
ated
risk
for t
risom
y
Nicolaides K et al. Ult Obstet Gynecol. 2013 (in press)
Prospective NIPT trial
Would you offer cfDNA tests to woman with a CT risk of 1:1500
and mild ventriculomegaly?
Q7
What should I do with a high-risk cfDNA result in a 20yr old
woman with normal NT?
Q8
How about twin pregnancy and fetal sexing on cfDNA?
Q9
Twin pregnancy FP rate of 1:500 (0.2%)
Sensitivity of 95%
Best available screen
Fetal sexing FP rate of 1:250 (0.4%)
OAPR of 20%
IONA test: X-depletion
Should we check for fetal microdeletions on cfDNA?
Q10
22q11 microdeletions 1:4000 births
Variable expressivity
Screening criteria met?
Testing efficiency FP rate of 1:200 (0.5%)
OAPR about 20%
Sensitivity unknown
Implementing the SAFE test in the NHS
Thank you
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