1.
Predizione e
prevenzione
della
preeclampsia
Adriana Valcamonico
Dipartimento di Ostetricia e Ginecologia
Università di Brescia
A.O. Spedali Civili di Brescia

2.
Preeclampsia
• Seconda causa diretta di morte materna
• 70-80.000 morti materne/anno
• 500.000 morti perinatali/anno
• 99% in Paesi in via di sviluppo
(Asia e Africa sub-sahariana)
Pre-eclampsia: An Update
Peter von Dadelszen & Laura A. Magee
Published online: 12 June 2014
# Springer Science+Business Media New York 2014
Abstract Pre-eclampsia remains the second leadi
cause of maternal death, >99 % of which occur
developed countries. Over 90 percent of the observe
tion in pre-eclampsia-related maternal deaths in
(1952–2008) occurred with antenatal surveillance a
delivery. In this review, we discuss the pathogenesis,
tic criteria, disease prediction models, prevention a
agement of pre-eclampsia. The Pre-eclampsia Integra
mate of RiSk (PIERS) models and markers of an
imbalance identify women at incremental risk for se
eclampsia complications. For women at high risk of
ing pre-eclampsia, low doses of aspirin (especially
<17 weeks) and calcium are evidence-based prev
strategies; heparin is less so. Severe hypertension
treated and the Control of Hypertension In Pr
(CHIPS) Trial (reporting: 2014) will guide non-seve
tension management. Magnesium sulfate prevents a
eclampsia; there is insufficient evidence to support a
regimens. Pre-eclampsia predicts later cardiovascula
however, at this time we do not know what to do ab
This article is part of the Topical Collection on Hypertensive Em
P. von Dadelszen (*) : L. A. Magee
Department of Obstetrics and Gynaecology, University of Bri
Columbia, Rm V3-339, 950 West 28th Avenue, Vancouver,
BC V5Z 4H4, Canada
e-mail: pvd@cw.bc.ca
L. A. Magee
e-mail: LMagee@cw.bc.ca
Curr Hypertens Rep (2014) 16:454
The Global Impact of Pre-eclampsia and Eclampsia
Lelia Duley, MD
Over half a million women die each year from pregnancy related causes, 99% in low and middle
income countries. In many low income countries, complications of pregnancy and childbirth are
the leading cause of death amongst women of reproductive years. The Millennium Develop-
ment Goals have placed maternal health at the core of the struggle against poverty and
inequality, as a matter of human rights. Ten percent of women have high blood pressure during
pregnancy, and preeclampsia complicates 2% to 8% of pregnancies. Preeclampsia can lead to
problems in the liver, kidneys, brain and the clotting system. Risks for the baby include poor
growth and prematurity. Although outcome is often good, preeclampsia can be devastating and
life threatening. Overall, 10% to 15% of direct maternal deaths are associated with preeclamp-
sia and eclampsia. Where maternal mortality is high, most of deaths are attributable to
eclampsia, rather than preeclampsia. Perinatal mortality is high following preeclampsia, and
even higher following eclampsia. In low and middle income countries many public hospitals
have limited access to neonatal intensive care, and so the mortality and morbidity is likely to be
considerably higher than in settings where such facilities are available. The only interventions
shown to prevent preeclampsia are antiplatelet agents, primarily low dose aspirin, and calcium
supplementation. Treatment is largely symptomatic. Antihypertensive drugs are mandatory for
very high blood pressure. Plasma volume expansion, corticosteroids and antioxidant agents
have been suggested for severe preeclampsia, but trials to date have not shown benefit.
Optimal timing for delivery of women with severe preeclampsia before 32 to 34 weeks’
gestation remains a dilemma. Magnesium sulfate can prevent and control eclamptic seizures.
For preeclampsia, it more than halves the risk of eclampsia (number needed to treat 100, 95%
confidence interval 50 to 100) and probably reduces the risk of maternal death. A quarter of
women have side effects, primarily flushing. With clinical monitoring serious adverse effects
are rare. Magnesium sulfate is the anticonvulsant of choice for treating eclampsia; more
effective than diazepam, phenytoin, or lytic cocktail. Although it is a low cost effective treat-
ment, magnesium sulfate is not available in all low and middle income countries; scaling up its
use for eclampsia and severe preeclampsia will contribute to achieving the Millennium Devel-
opment Goals.
Semin Perinatol 33:130-137 © 2009 Elsevier Inc. All rights reserved.
KEYWORDS pre-eclampsia, prevention, treatment, maternal mortality, maternal health
Every maternal death is a tragedy for the woman and for her
family, and a loss to the community and society in which
she lives. Over half a million women die each year from preg-
nancy-related causes, and 99% of these deaths occur in low- and
middle-income countries (Fig. 1).1 In many low-income coun-
tries, complications of pregnancy and childbirth are the leading
tality and ill-health have made little progress. In some, the situ-
ation has actually worsened over recent years.1 Globally, little
progress has been made in saving mothers’ lives.2
Pre-eclampsia and eclampsia remain important causes of ma-
ternal and perinatal mortality and morbidity. This chapter sum-
marizes the global problems associated with these potentially
Semin Perinatol 33:130-137, 2009

3.
«Despite significant advances in our understanding of the complex pathogenesis of
preeclampsia, our ability to predict and prevent it lag far behind»
Nonostante i significativi miglioramenti delle nostre
conoscenze nella complessa patogenesi della
preeclampsia, la nostra abilità nel predirla e
prevenirla è ancora quanto mai scarsa.

4.
The ability to predict the most severe forms of preeclampsia would allow:
- closer surveillance
- prevention
- earlier intervention on maternal health.
La capacità di predire le forme più severe di
preeclampsia permetterebbe:
- una sorveglianza più stretta
- una prevenzione
- interventi precoci e mirati per la salute materna

5.
This is especially important at a time when there is increasing evidence of
preeclampsia’s devastating impact on the mother’s long term health.
Cardiology in Review 2010;18:178
Questo è particolarmente importante laddove
vi è ormai una chiara evidenza che la
preeclampsia può avere un impatto
significativamente negativo a lungo termine
sulla salute materna.

6.
2007

7.
Bellamy L, et al:
Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and metal-analysis.
BMJ 335:974, 2007
Esiti a lungo termine della PE: ipertensione

8.
Esiti a lungo termine della PE: cardiopatia ischemica
Bellamy L, et al:
Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and metal-analysis.
BMJ 335:974, 2007

9.
Esiti a lungo termine della PE: cardiopatia ischemica
Bellamy L, et al: Pre-eclampsia and risk of cardiovascular disease and cancer in later
life: Systematic review and metal-analysis.
BMJ 335:974, 2007

10.
Thus no one test is truly predictive of
preeclampsia, though some tests are useful to
detect patient at risk.
The multifactorial origin of preeclampsia
suggests that is highly unlikely that there will be
one universal predictive test in the future.
G. Dekker and B. Sibai
Primary, secondary and tertiary prevention of preeclampsia.
Lancet 2001;357:209.
It is becoming increasingly clear that it is unlikely to
find a single screening test that meets the requisite
sensitivity and specificity and cost effectiveness profile.
Use of multiparametric tests using multiple biomarkers
that reflect different aspects of the complex pathological
processes involved in preeclampsia is a sensible approach.
Prediction of Preeclampsia-Bench to Bedside
Anjali Acharya & Wunnie Brima & Shivakanth Burugu &
Tanvi Rege
Published online: 21 September 2014
# Springer Science+Business Media New York 2014
Abstract Hypertensive disorders of pregnancy (HDP) con-
stitute the most common medical condition seen during ges-
tation, effecting 1 in 10 pregnancies in the USA. Traditionally,
preeclampsia (PE) is defined as a new onset of hypertension
and either proteinuria or end-organ dysfunction after 20 weeks
of gestation in a previously normotensive woman. Preeclamp-
sia is a potentially life-threatening condition with widespread
underlying endothelial dysfunction, and accompanying in-
flammation, vasoconstriction, and platelet activation. Women
with preeclampsia are at an increased risk for life-threatening
complications and progression to eclampsia. Worldwide, 10 to
15 % of maternal deaths are from preeclampsia and related
complications. Traditionally, diagnosis of preeclampsia is
made based upon presence of risk factors and clinical criteria.
Diagnosis is challenging in asymptomatic women early in
pregnancy as well as in nulliparous women as they lack
obstetric history; however, it is well known that women with
previous preeclampsia have a 14.7 % risk of the condition in
the second pregnancy. Prediction of those at risk and early
diagnosis is crucial to enable close surveillance of high-risk
women in order to improve maternal and fetal outcomes.
newer systems biology approaches to give us better insight
into the pathogenesis of the disease.
Keywords Preeclampsia . Early onset preeclampsia (EoPE) .
Late onset preeclampsia (LoPE) . Systems biology .
Multiparametric testing . Epigenetics
Introduction
Hypertensive disorders of pregnancy (HDP) constitute the
most common medical condition during gestation, impacting
1 in 10 pregnancies in the USA and a much higher number in
the developing countries. The National High Blood Pressure
Education Program of the NHLBI and the American College
of Obstetricians and Gynecologists (ACOG) [1] classifies
HDP into four major categories: preeclampsia/eclampsia,
chronic hypertension, gestational hypertension, and preeclamp-
sia superimposed upon chronic/preexisting hypertension.
Hypertension in pregnancy is defined as systolic blood
pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg
Curr Hypertens Rep (2014) 16:491

11.
Quali strumenti abbiamo per identificare la
popolazione a rischio di preeclampsia?
•Fattori di rischio materni
•Metodi biofisici: velocimetria arterie uterine
•Metodi biochimici: markers sierici

12.
NICE 2010oring
Risk factors for pre-eclampsia
Moderate
● First pregnancy
● Age ≥ 40 years
● Pregnancy interval > 10 years
● BMI ≥ 35 kg/m2 at first visit
● Family history of pre-eclampsia
● Multiple pregnancy
High
● Hypertensive disease during
previous pregnancy
● Chronic kidney disease
● Autoimmune disease such as
systemic lupus erythematosis
or antiphospholipid syndrome
● Type 1 or type 2 diabetes
● Chronic hypertension
AIPE 2013

13.
ISSHP 2018 ACOG 2019

14.
Velocimetria della circolazione uterina

15.
Doppler uterine waveform reflects
trophoblastic invasion
20-24 w
10-14 w

16.
Accuratezza della velocimetria Doppler nella predittività della preeclampsia
A.T.Papageorghiou et al. The role of uterine artery Doppler in predicting adverse
pregnancy outcome. Best Practice & Res. Clin. Obstet.Gynecol. 2004; 18: 383.

17.
In the prediction of preeclampsia requiring delivery before 34 weeks,
Doppler at 20–23 weeks gestation performs well, showing a detection rate
of about 80%.
Secondo trimestre
TABLE 2. Sensitivity of Uterine Artery Doppler in the Second Trimester for Preeclampsia and
IUGR Requiring Delivery at <34 wk
N n Preeclampsia n IUGR*
Albaiges et al13
1757 8/10 80% 7/10 70%
Yu et al14
32,157 122/158 77% 9/37 44%
Onwudiwe et al15
w 3347 22/23 96% 100/366 27%
*IUGR without preeclampsia.
wScreening FPR of 10%. Numbers indicate those detected using PI alone. With inclusion of maternal history and mean arterial
pressure (MAP), detectionofPreeclampsiawas100%. Detection ofIUGR requiringpreterm deliverywasnotdiscussedand27%
represents detection of all patients with IUGR regardless of GA at delivery.
n indicates Number of cases predicted/Number of cases that occurred.
Uterine Artery Doppler and Prediction of Preeclampsia 893

18.
2nd trimester screening
Too late for prophylaxis
The potential advantage of earlier identification of
a high risk group might make prophylactic
interventions more effective
Doppler-velocimetria delle arterie uterine

19.
1st vs 2nd trimester uterine artery Doppler
Martin AM, Bindra R, Curcio P, et al. Screening for pre-eclampsia and fetal growth
restriction by uterine artery Doppler at 11-14 weeks of gestation.
Ultrasound in Obstetrics and Gynecology 2001; 18: 583-586.

20.
Cnossen, J. S. et al. CMAJ 2008;178:701-711
74 studies of preeclampsia
total 79 547 patientspatients at low risk

21.
«I da% disponibili suggeriscono che la velocimetria Doppler delle
arterie uterine a 20 se9mane sia comunque da raccomandare alle
gestanB ad alto rischio per disordini ipertensivi o insufficienza
placentare.»
«L’impiego della velocimetria Doppler delle arterie uterine nelle
nullipare è dibaFuto, in quanto il test eseguito a 20 se9mane nel
contesto dell’ecografia di screening ha un alto valore predi9vo
nega%vo, ma un basso valore predi9vo posi%vo e comporta la
necessità di rivalutare le pazien% dopo 24 se9mane quando la
placentazione si è completata.»
LINEE GUIDA SIEOG 2015

22.
Markers sierici

23.
Cetin I, 2011
The placenta produces a number of proteins which can be found in the maternal
bloodstream
Altered placental function may cause changes in concentration of these proteins
in maternal serum
PlGF
sFlt-1
Endoglina

24.
PlGF
VEGF
Pathogenesis of pre-eclampsia is considered to be related to an imbalance
between proangiogenic factors, such as VEGF or placental growth factor
(PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine
kinase 1 (sFlt-1) and the soluble form of endoglin.
sFlt-1
endoglina

25.
Levine RJ,. N Engl J Med 2004; 350:672-683
Decreased levels of PlGF predict the subsequent
development of preeclampsia

26.
Levine RJ,. N Engl J Med 2004; 350:672-683
Increased levels of sFlt-1 predict the subsequent
development of preeclampsia
n sFlt-1: increased in the placenta and blood of women with preeclampsia and who
later will develop preclampsia
n Levels were higher in preeclampsia with onset before 37 weeks than in preeclampsia of later
onset; in severe as compared with mild preeclampsia; and in preeclampsia with delivery of a
small rather than appropriate-for-gestational-age infant

27.
BJOG 2012
Author’s conclusions
PlGF, sFLT1, VEGF and sENG showed modest but
significantly different concentrations before 30 weeks of
gestation in women who developed pre-eclampsia.
Test accuracies of all four markers, however, are too poor for
accurate prediction of pre-eclampsia in clinical practice.

28.
Thus, biomarkers and ultrasonography cannot
accurately predict preeclampsia and should
remain investigational.
VOL. 133, NO. 1, JANUARY 2019

29.
ISSHP supports first trimester screening for
preeclampsia when this can be integrated into the
local health system although the cost effectiveness
of this approach remains to be established.
Predicting the Development of Preeclampsia
ISSHP 2017

30.
It is becoming increasingly clear that it is unlikely to find a single screening
test that meets the requisite sensitivity and specificity and cost
effectiveness profile
Use of multiparametric tests using multiple biomarkers that reflect different
aspects of the complex pathological processes involved in preeclampsia is a
sensible approach.
Multimarker combination tests with high detection rates and low false-
positive rates seem very effective.
Curr Hypertens Rep (2014) 16:491

31.
Fax +41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
Competing Risks Model in Early
Screening for Preeclampsia by
Biophysical and Biochemical Markers
Ranjit Akolekarb, d Argyro Syngelakib–d Leona Poonb David Wrighta
Kypros H. Nicolaidesb, c
a
School of Computing and Mathematics, Plymouth University, Plymouth, b
Harris Birthright Research Centre of
Fetal Medicine, King’s College Hospital, and c
Department of Fetal Medicine, University College Hospital, London,
and d
Department of Fetal Medicine, Medway Maritime Hospital, Gillingham, UK
ery and therefore the deviation from normal was greater for
early than late PE for all four biomarkers. Screening by ma-
ternal characteristics, biophysical and biochemical markers
detected 96% of cases of PE requiring delivery before 34
weeks and 54% of all cases of PE at a fixed false-positive rate
of 10%. Conclusions: A new model has been developed for
effective first-trimester screening for PE.
Copyright © 2012 S. Karger AG, Basel
Introduction
Preeclampsia (PE), which affects about 2% of preg-
nancies, is a major cause of maternal and perinatal mor-
bidity and mortality [1–3]. The prevalence of PE can po-
tentially be halved by a strategy of early identification of
the high-risk group and the prophylactic use of aspirin
[4–6]. Algorithms combining maternal demographic
characteristics and medical and obstetric history with
biophysical and biochemical markers at 11–13 weeks’
gestation have been developed for the prediction of early
or late PE on the basis of whether or not delivery occurs
before 34 weeks’ gestation [7, 8]. However, we have re-
Key Words
First-trimester screening ؒ Preeclampsia ؒ Uterine artery
Doppler ؒ Mean arterial pressure ؒ Placental growth factor ؒ
Pyramid of pregnancy care
Abstract
Objective: To develop models for prediction of preeclamp-
sia (PE) based on maternal characteristics, biophysical and
biochemical markers at 11–13 weeks’ gestation in which the
gestation at the time of delivery for PE is treated as a con-
tinuous variable. Methods: This was a screening study of sin-
gleton pregnancies at 11–13 weeks including 1,426 (2.4%)
that subsequently developed PE and 57,458 that were unaf-
fected by PE. We developed a survival time model for the
time of delivery for PE in which Bayes’ theorem was used to
combine the prior information from maternal characteristics
with uterine artery pulsatility index (PI), mean arterial pres-
sure (MAP), serum pregnancy-associated plasma protein-A
(PAPP-A) and placental growth factor (PLGF) multiple of the
median (MoM) values. Results: In pregnancies with PE, there
was a linear correlation between MoM values of uterine ar-
tery PI, MAP, PAPP-A and PLGF with gestational age at deliv-
Prof. K.H. Nicolaides
Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital
Denmark Hill
London SE5 9RS (UK)
Tel. +44 203 299 8256, E-Mail kypros.nicolaides @ kcl.ac.uk
© 2012 S. Karger AG, Basel
1015–3837/13/0331–0008$38.00/0
Accessible online at:
www.karger.com/fdt
Downloadedby:
91.252.80.115-9/18/20179:24:28AM
Competing
Screening f
Biophysical
Ranjit Akolekarb, d
Ar
Kypros H. Nicolaidesb,
a
School of Computing and Mat
Fetal Medicine, King’s College H
and d
Department of Fetal Med
Key Words
First-trimester screening ؒ P
Table 3. Estimated detection rates of PE requiring delivery before 34, 37 and 42 weeks’ gestation, at false-positive rates (FPR) of 5 and 10%
Screening test FPR
%
PE
<34 weeks (n = 214)
PE
<37 weeks (n = 568)
PE
<42 weeks (n = 1,426)
risk
cutoff
detection
n (%)
risk
cutoff
detection
n (%)
risk
cutoff
detection
n (%)
Maternal characteristics 5.0 1:93 78 (35.5) 1:35 186 (32.7) 1:9 419 (29.4)
10.0 1:143 108 (50.5) 1:51 246 (43.3) 1:12 574 (40.3)
Uterine artery PI 5.0 1:88 127 (59.3) 1:31 227 (40.0) 1:9 445 (31.2)
10.0 1:164 161 (75.2) 1:52 313 (55.1) 1:12 602 (42.2)
MAP 5.0 1:88 125 (58.4) 1:31 250 (44.0) 1:8 532 (37.3)
10.0 1:159 156 (72.9) 1:52 337 (59.3) 1:12 763 (53.5)
PAPP-A 5.0 1:88 93 (43.6) 1:33 212 (37.3) 1:9 449 (31.5)
10.0 1:151 117 (54.7) 1:52 274 (48.2) 1:12 601 (42.1)
PLGF 5.0 1:95 127 (59.3) 1:33 232 (40.8) 1:9 415 (29.1)
10.0 1:170 155 (72.4) 1:55 309 (54.4) 1:12 572 (40.1)
Uterine artery PI and MAP 5.0 1:96 171 (79.9) 1:31 310 (54.6) 1:7 498 (34.9)
10.0 1:197 192 (89.7) 1:57 406 (71.5) 1:12 807 (56.6)
PAPP-A and PLGF 5.0 1:101 129 (60.3) 1:34 243 (42.8) 1:9 433 (30.4)
10.0 1:181 159 (74.3) 1:56 317 (55.8) 1:12 582 (40.8)
Table3.EstimateddetectionratesofPErequiringdeliverybefore34,37and42weeks’gestation,atfalse-positiverates(FPR)of5and10%
Screeningtest FPR
%
PE
<34weeks(n=214)
PE
<37weeks(n=568)
PE
<42weeks(n=1,426)
risk
cutoff
detection
n(%)
risk
cutoff
detection
n(%)
risk
cutoff
detection
n(%)
Maternalcharacteristics 5.0 1:93 78(35.5) 1:35 186(32.7) 1:9 419(29.4)
10.0 1:143 108(50.5) 1:51 246(43.3) 1:12 574(40.3)
UterinearteryPI 5.0 1:88 127(59.3) 1:31 227(40.0) 1:9 445(31.2)
10.0 1:164 161(75.2) 1:52 313(55.1) 1:12 602(42.2)
MAP 5.0 1:88 125(58.4) 1:31 250(44.0) 1:8 532(37.3)
10.0 1:159 156(72.9) 1:52 337(59.3) 1:12 763(53.5)
PAPP-A 5.0 1:88 93(43.6) 1:33 212(37.3) 1:9 449(31.5)
10.0 1:151 117(54.7) 1:52 274(48.2) 1:12 601(42.1)
PLGF 5.0 1:95 127(59.3) 1:33 232(40.8) 1:9 415(29.1)
10.0 1:170 155(72.4) 1:55 309(54.4) 1:12 572(40.1)
UterinearteryPIandMAP 5.0 1:96 171(79.9) 1:31 310(54.6) 1:7 498(34.9)
10.0 1:197 192(89.7) 1:57 406(71.5) 1:12 807(56.6)
PAPP-AandPLGF 5.0 1:101 129(60.3) 1:34 243(42.8) 1:9 433(30.4)
10.0 1:181 159(74.3) 1:56 317(55.8) 1:12 582(40.8)
UterinearteryPI,MAPandPAPP-A 5.0 1:105 175(81.8) 1:26 298(52.5) 1:7 514(36.0)
10.0 1:216 198(92.5) 1:65 424(74.6) 1:12 811(59.9)
UterinearteryPI,MAPandPLGF 5.0 1:126 187(87.4) 1:36 344(60.6) 1:8 536(37.6)
10.0 1:261 205(95.8) 1:67 439(77.3) 1:12 755(52.9)
UterinearteryPI,MAP,PAPP-AandPLGF 5.0 1:128 200(93.4) 1:36 347(61.1) 1:8 539(37.8)
10.0 1:269 206(96.3) 1:67 435(76.6) 1:12 764(53.6)
Conclusions: A new model has been developed for effective first-trimester screening for PE.
August 16, 2012
Approx 60.000 singleton pregancies

32.
Multicenter screening for pre-eclampsia by maternal factors
and biomarkers at 11–13 weeks’ gestation: comparison with
NICE guidelines and ACOG recommendations
N. O’GORMAN1
, D. WRIGHT2
, L. C. POON1,3#
, D. L. ROLNIK1
, A. SYNGELAKI1
,
M. DE ALVARADO1,4
, I. F. CARBONE5
, V. DUTEMEYER6
, M. FIOLNA1,7
, A. FRICK1,8
,
N. KARAGIOTIS1
, S. MASTRODIMA1,9
, C. DE PACO MATALLANA10
, G. PAPAIOANNOU11
,
A. PAZOS12
, W. PLASENCIA13
and K. H. NICOLAIDES1#
1Harris Birthright Center for Fetal Medicine, King’s College Hospital, London, UK; 2Institute of Health Research, University of Exeter,
Exeter, UK; 3Chinese University of Hong Kong, Hong Kong, China; 4Homerton University Hospital, London, UK; 5Ospedale Maggiore
Policlinico, Milan, Italy; 6Centre Hospitalier Universitaire Brugmann, Universit´e Libre de Bruxelles, Brussels, Belgium; 7Medway Maritime
Hospital, Gillingham, UK; 8Lewisham University Hospital, London, UK; 9North Middlesex University Hospital, London, UK; 10Hospital
Cl´ınico Universitario Virgen de la Arrixaca, Murcia, Spain; 11Attikon University Hospital, Athens, Greece; 12Hospital Universitario San
Cecilio, Granada, Spain; 13Hospiten Group, Tenerife, Canary Islands, Spain
KEYWORDS: Bayes’ theorem; first-trimester screening; mean arterial pressure; placental growth factor; pre-eclampsia;
pregnancy-associated plasma protein-A; pyramid of pregnancy care; survival model; uterine artery Doppler
ABSTRACT
Objective To compare the performance of screening for
pre-eclampsia (PE) based on risk factors from medical
history, as recommended by NICE and ACOG, with
the method proposed by The Fetal Medicine Foundation
(FMF), which uses Bayes’ theorem to combine the a-priori
risk from maternal factors, derived by a multivariable
logistic model, with the results of various combinations
of biophysical and biochemical measurements.
Methods This was a prospective multicenter study of
screening for PE in 8775 singleton pregnancies at
11–13 weeks’ gestation. A previously published FMF
algorithm was used for the calculation of patient-specific
risk of PE in each individual. The detection rates (DRs)
and false-positive rates (FPRs) for delivery with PE
< 32, < 37 and ≥ 37 weeks were estimated and compared
with those derived from application of NICE guidelines
and ACOG recommendations. According to NICE, all
high-risk pregnancies should be offered low-dose aspirin.
According to ACOG, use of aspirin should be reserved
for women with a history of PE in at least two
previous pregnancies or PE requiring delivery < 34 weeks’
gestation.
Results In the study population, 239 (2.7%) cases
180 (2.1%) developed PE < 32, < 37 and ≥ 37 weeks,
respectively. Screening with use of the FMF algorithm
based on a combination of maternal factors, mean arterial
pressure (MAP), uterine artery pulsatility index (UtA-PI)
and serum placental growth factor (PlGF) detected 100%
(95% CI, 80–100%) of PE < 32 weeks, 75% (95% CI,
62–85%) of PE < 37 weeks and 43% (95% CI, 35–50%)
of PE ≥ 37 weeks, at a 10.0% FPR. Screening with use of
NICE guidelines detected 41% (95% CI, 18–67%) of PE
< 32 weeks, 39% (95% CI, 27–53%) of PE < 37 weeks
and 34% (95% CI, 27–41%) of PE ≥ 37 weeks, at 10.2%
FPR. Screening with use of ACOG recommendations
detected 94% (95% CI, 71–100%) of PE < 32 weeks,
90% (95% CI, 79–96%) of PE < 37 weeks and 89%
(95% CI, 84–94%) of PE ≥ 37 weeks, at 64.2% FPR.
Screening based on the ACOG recommendations for
use of aspirin detected 6% (95% CI, 1–27%) of PE
< 32 weeks, 5% (95% CI, 2–14%) of PE < 37 weeks
and 2% (95% CI, 0.3–5%) of PE ≥ 37 weeks, at 0.2%
FPR.
Conclusion Performance of screening for PE at
11–13 weeks’ gestation by the FMF algorithm using a
combination of maternal factors, MAP, UtA-PI and PlGF,
is by far superior to the methods recommended by NICE
and ACOG. Copyright © 2017 ISUOG. Published by
Ultrasound Obstet Gynecol 2017; 49: 756–760

33.
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.17455
Multicenter screening for pre-eclampsia by maternal factors
and biomarkers at 11–13 weeks’ gestation: comparison with
NICE guidelines and ACOG recommendations
N. O’GORMAN1
, D. WRIGHT2
, L. C. POON1,3#
, D. L. ROLNIK1
, A. SYNGELAKI1
,
M. DE ALVARADO1,4
, I. F. CARBONE5
, V. DUTEMEYER6
, M. FIOLNA1,7
, A. FRICK1,8
,
N. KARAGIOTIS1
, S. MASTRODIMA1,9
, C. DE PACO MATALLANA10
, G. PAPAIOANNOU11
,
A. PAZOS12
, W. PLASENCIA13
and K. H. NICOLAIDES1#
1Harris Birthright Center for Fetal Medicine, King’s College Hospital, London, UK; 2Institute of Health Research, University of Exeter,
Exeter, UK; 3Chinese University of Hong Kong, Hong Kong, China; 4Homerton University Hospital, London, UK; 5Ospedale Maggiore
Policlinico, Milan, Italy; 6Centre Hospitalier Universitaire Brugmann, Universit´e Libre de Bruxelles, Brussels, Belgium; 7Medway Maritime
Hospital, Gillingham, UK; 8Lewisham University Hospital, London, UK; 9North Middlesex University Hospital, London, UK; 10Hospital
Cl´ınico Universitario Virgen de la Arrixaca, Murcia, Spain; 11Attikon University Hospital, Athens, Greece; 12Hospital Universitario San
Cecilio, Granada, Spain; 13Hospiten Group, Tenerife, Canary Islands, Spain
KEYWORDS: Bayes’ theorem; first-trimester screening; mean arterial pressure; placental growth factor; pre-eclampsia;
pregnancy-associated plasma protein-A; pyramid of pregnancy care; survival model; uterine artery Doppler
ABSTRACT
Objective To compare the performance of screening for
pre-eclampsia (PE) based on risk factors from medical
history, as recommended by NICE and ACOG, with
the method proposed by The Fetal Medicine Foundation
(FMF), which uses Bayes’ theorem to combine the a-priori
risk from maternal factors, derived by a multivariable
logistic model, with the results of various combinations
of biophysical and biochemical measurements.
Methods This was a prospective multicenter study of
screening for PE in 8775 singleton pregnancies at
11–13 weeks’ gestation. A previously published FMF
algorithm was used for the calculation of patient-specific
risk of PE in each individual. The detection rates (DRs)
and false-positive rates (FPRs) for delivery with PE
< 32, < 37 and ≥ 37 weeks were estimated and compared
180 (2.1%) developed PE < 32, < 37 and ≥ 37 weeks,
respectively. Screening with use of the FMF algorithm
based on a combination of maternal factors, mean arterial
pressure (MAP), uterine artery pulsatility index (UtA-PI)
and serum placental growth factor (PlGF) detected 100%
(95% CI, 80–100%) of PE < 32 weeks, 75% (95% CI,
62–85%) of PE < 37 weeks and 43% (95% CI, 35–50%)
of PE ≥ 37 weeks, at a 10.0% FPR. Screening with use of
NICE guidelines detected 41% (95% CI, 18–67%) of PE
< 32 weeks, 39% (95% CI, 27–53%) of PE < 37 weeks
and 34% (95% CI, 27–41%) of PE ≥ 37 weeks, at 10.2%
FPR. Screening with use of ACOG recommendations
detected 94% (95% CI, 71–100%) of PE < 32 weeks,
90% (95% CI, 79–96%) of PE < 37 weeks and 89%
(95% CI, 84–94%) of PE ≥ 37 weeks, at 64.2% FPR.
Screening based on the ACOG recommendations for
use of aspirin detected 6% (95% CI, 1–27%) of PE
< 32 weeks, 5% (95% CI, 2–14%) of PE < 37 weeks
Conclusion
Performance of screening for PE at 11–
13weeks’ gestation by the FMF algorithm using a
combination of maternal factors, MAP, UtA-PI and
PlGF, is by far superior to the methods recommended
by NICE and ACOG
Ultrasound Obstet Gynecol 2017; 49: 756–760

34.
Profilassi farmacologica
§ Acidi grassi polinsaturi
§ Antiossidanti e vitamine
§ Calcio
Aspirina
Eparina

35.
Duley L et al. Antiplatelet agents for preventing preeclampsia and its
complications (Review) Cochrane Library 2007, Issue 4
2007
Fifty-nine trials (37,560 women) are
included in this review.
There is a 17% reduction in the risk of
pre-eclampsia associated with the use
of antiplatelet agents.

36.
“As most of the evidence related to low-dose
aspirin, this is the antiplatelet agent that
should be used in clinical practice for
prevention of preeclampsia”.
Duley L et al.
Antiplatelet agents for preventing preeclampsia and its complications (Review)
Cochrane Library 2007, Issue 4

37.
Which women are most likely to benefit
when treatment should be started
what dose
Authors’ conclusions
Duley L et al.
Antiplatelet agents for preventing preeclampsia and its complications (Review)
Cochrane Library 2007, Issue 4

38.
… in high-risk women the effect of aspirin for the prevention of PE,
severe PE, and FGR is dose-dependent
Quali dosi utilizzare?

39.
… in high-risk women the effect of aspirin for the prevention of PE, severe
PE, and FGR is optimal when initiated before 16 weeks of gestation.
Quando iniziare?

40.
ACOG 2018
81 mg/die

41.
ISSHP 2018

42.
gh risk of pre-eclampsia
Antenatal care and fetal monitoring
Risk factors for pre-eclampsia
Moderate
● First pregnancy
● Age ≥ 40 years
● Pregnancy interval > 10 years
● BMI ≥ 35 kg/m2 at first visit
● Family history of pre-eclampsia
● Multiple pregnancy
High
● Hypertensive disease during
previous pregnancy
● Chronic kidney disease
● Autoimmune disease such as
systemic lupus erythematosis
or antiphospholipid syndrome
● Type 1 or type 2 diabetes
● Chronic hypertension
Advise woman to take aspirin*
75 mg/day from 12 weeks until birth.
If at least two
moderate risk
factors or at
least one high
risk factor for
pre-eclampsia
wth
t
ous
lier
NICE 2010

43.
Al momento attuale l’unico presidio consigliabile per
la prevenzione della preeclampsia in pazienti
selezionate è:
- l’aspirina
- ad un dosaggio di 100 mg/die (meglio se in
somministrazione serale)
- iniziata ad un’epoca inferiore alle 16 settimane
AIPE 2013

44.
Eparina

45.
eparina
Secondaryoutcomes
The incidence of serious adverse events, including pregnancy
complications different from primary outcomes and treatment-
and in 12 controls (3 at 20th, 6 at 28th, and 3 at 36th weeks of
gestation). Time to delivery and the number of cesarean sections
did not differ between groups (Table 4). Independent of treatment
allocation,thebirthweightwasbelowthe10thcentilein24.6%of
Table2.Latepregnancycomplicationsinstudyparticipantsavailableforprimaryoutcomeanalysis,accordingtotreatmentarm
Nadroparinandmedical
surveillance(n ‫؍‬ 63)
Medicalsurveillance
alone(n ‫؍‬ 65)
Absoluterisk
difference(95%CI) P
Recurrentpregnancycomplications,n(%) 13 (20.6) 12 (18.5) 2.2 (Ϫ11.6 to 16.0) .76
Preeclampsia 5 (7.9) 3 (4.6) 3.3 (Ϫ5.9 to 13.1) .44
Eclampsia 0 0 NA NA
HELLPsyndrome 1 (1.6) 0 1.6 (Ϫ4.2 to 8.5) .49
Intrauterinefetaldeath 2 (3.2) 1 (1.5) 1.6 (Ϫ5.4 to 9.4) .62
FGR 5 (7.9) 7 (10.8) Ϫ2.8 (Ϫ13.6 to 8.0) .58
Placentalabruption 0 1 (1.5) Ϫ1.5 (Ϫ8.2 to 4.3) 1.0
NAindicatesnotapplicable.
CONCLUSIONS
Nadroparin did not prevent late pregnancy complications in women at risk
of recurrence.
Antithrombotic prophylaxis should not be routinely administered to prevent
recurrences of placenta mediated pregnancy complications.
Ida Martinelli et al. for the HAPPY Study Group
BLOOD, 5 APRIL 2012

46.
Alltrials Multicentretrials Single-centretrials
LMWH
(n=480)
NoLMWH
(n=483)
Absolutedifference
(95%CI),pvalue
LMWH
(n=288)
NoLMWH
(n=291)
Absolutedifference
(95%CI),pvalue
LMWH
(n=192)
NoLMWH
(n=192)
Absolutedifference
(95%CI),pvalue
Primarycompositeoutcomeofearly-onsetorsevere
pre-eclampsia,orSGA<5thpercentile,orplacental
abruption,orpregnancyloss≥20weeks’gestation*
62/444
(14%)
95/433
(22%)
–8·0%(–17·3to
1·4),p=0·09
47/263
(18%)
47/255
(18%)
–0·6%(–10·4to9·2),
p=0·91
15/181
(8%)
48/178
(27%)
–18·7%(95%CI
–21·6to–15·7),
p<0·0001
Secondaryoutcomes
Placentalabruption 15/469
(3%)
31/474
(7%)
–3·3%(–6·7to
–0·1),p=0·0491
5/277
(2%)
7/282
(2%)
–0·7%(–4·0to2·6),
p=0·69
10/192
(5%)
24/192
(13%)
–7·3%(–9·0to–5·6),
p<0·0001
Placentalabruptionleadingtodelivery 5/469
(1%)
10/474
(2%)
–1·0%(–2·4to0·3),
p=0·14
3/277
(1%)
5/282
(2%)
† 2/192
(1%)
5/192
(3%)
†
Lancet 2016; 388: 2629–41
Published Online
October 6, 2016
http://dx.doi.org/10.1016/
S0140-6736(16)31139-4
See Comment page 2570
*Members listed at end of the
report
Ottawa Blood Disease Center,
(Prof M A Rodger MD) and
Centre for Practice-Changing
Research (N J Langlois MSc,
T Ramsay PhD, R Mallick PhD,
A D Mayhew MSc), Ottawa
Hospital Research Institute,
University of Ottawa, Ottawa,
ON, Canada; Consultations et
Laboratoire d’Hématologie et
Délégation à la Recherche
Clinique et à l’Innovation,
Nîmes cédex 09, France
(Prof J-C Gris MD); Department
of Obstetrics and Gynaecology
(Prof J I P de Vries MD,
M E van Hoorn MD,
C N H Abheiden MD) and
Department of Epidemiology
and Biostatistics
(P D Bezemer PhD),
VU University Medical Center,
Amsterdam, Netherlands;
A. Bianchi Bonomi Hemophilia
and Thrombosis Center,
Fondazione IRCCS Ca’
Granda–Ospedale Maggiore
Policlinico, Milan, Italy
(I Martinelli MD); CHU
Ste-Justine, Montreal, QC,
Canada (É Rey MD); Jena
University Hospital,
Department of Obstetrics and
Gynaecology, Jena, Germany
(Prof E Schleussner MD);
Academic Medical Center,
Department of Vascular
Medicine, Meibergdreef 9,
Amsterdam, the Netherlands
(Prof S Middeldorp MD); Turku
University, Turku University
Hospital, Åbo, Finland
(Prof R Kaaja MD); Department
of Medicine, McMaster
University, Hamilton, ON,
Canada (Prof S M Bates MD);
Laboratorio di Biostatistica,
Low-molecular-weight heparin and recurrent placenta-
mediated pregnancy complications: a meta-analysis of
individual patient data from randomised controlled trials
Marc A Rodger, Jean-Christophe Gris, Johanna I P de Vries, Ida Martinelli, Évelyne Rey, Ekkehard Schleussner, Saskia Middeldorp, Risto Kaaja,
Nicole J Langlois, Timothy Ramsay, Ranjeeta Mallick, Shannon M Bates, Carolien N H Abheiden, Annalisa Perna, David Petroff, Paulien de Jong,
Marion E van Hoorn, P Dick Bezemer, Alain D Mayhew, for the Low-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications
Study Group*
Summary
Background Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental
abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal,
fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence
in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous
study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-
mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to
trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-
molecular-weight heparin, we did an individual patient data meta-analysis.
Methods We did a systematic review in May, 2013, which identified eight eligible randomised trials done between
2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We
excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of
participants, intervention stopped too early, and no response from the principal investigator. We requested individual
patient data from the study authors for eligible women (women pregnant at the time of the study with a history of
previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption,
birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks’ gestation, or two losses after 12 weeks’
gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite
of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss
(≥20 weeks’ gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed
risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249.
Findings We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight
heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial
enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age
of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin
did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight
heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference –8%, 95% CI –17·3 to
1·4, p=0·09; relative risk 0·64, 95% CI 0·36–1·11, p=0·11). We noted significant heterogeneity between single-centre
and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary
outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications.
Interpretation Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated
pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the
power of our study to explore.
Funding Canadian Institutes of Health Research.
Introduction
Placenta-mediated pregnancy complications, including
pre-eclampsia, birth of a small-for-gestational-age (SGA)
neonate, placental abruption, or late pregnancy loss are
common and lead to substantial maternal and fetal
or neonatal morbidity and mortality.1–3
The risk of
recurrent placenta-mediated pregnancy complications in
subsequent pregnancies is important,4–6
and these
complications might be multiple (for example, both pre-
eclampsia and SGA), and not solely a repeat of
the placenta-mediated complication in a previous
pregnancy.4–6
No highly effective preventive strategies for use in
subsequent pregnancies exist. Aspirin offers small risk
reductions in patients with previous pre-eclampsia and
SGA; however, it might be more effective at reducing risk
Lancet 2016; 388: 2629–41
arin and recurrent placenta-
lications: a meta-analysis of
m randomised controlled trials
rtinelli, Évelyne Rey, Ekkehard Schleussner, Saskia Middeldorp, Risto Kaaja,
Bates, Carolien N H Abheiden, Annalisa Perna, David Petroff, Paulien de Jong,
w-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications
cations include pre-eclampsia, late pregnancy loss, placental
Labor
Délég
Cliniq
Nîme
(Prof
ofOb
(Prof
M E v
C N H
Depa
and B
(P D B
VUU
Amst
A. Bia
andT
Fond
Grand
Policl
(I Mar
Ste-Ju
Canad
Unive
Depa
Gyna
(Prof
previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption,
birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks’ gestation, or two losses after 12 weeks’
gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite
of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss
(≥20 weeks’ gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed
risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249.
Findings We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight
heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial
enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age
of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin
did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight
heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference –8%, 95% CI –17·3 to
1·4, p=0·09; relative risk 0·64, 95% CI 0·36–1·11, p=0·11). We noted significant heterogeneity between single-centre
and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary
outcomeinwomenwithpreviousabruption(p=0·006)butnotinanyoftheothersubgroupsofpreviouscomplications.
Interpretation Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated
pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the
power of our study to explore.
eparina

47.
Bassam Haddad, MD, et al. for the Heparin-Preeclampsia (HEPEPE) Trial Investigators*
Table 3. Results—Primary and Secondary Outcomes
Enoxaparin–
Aspirin
(n5122)
Aspirin
Alone
(n5122) RR (95% CI) ARR (%) (95% CI) P
Primary outcome
Composite morbidity 42 (34.4) 50 (41.0) 0.84 (0.61–1.16) 6.5 (26.6 to 18.7) .29
Secondary outcomes
Elements of composite
morbidity
Preeclampsia 22 (18.0) 27 (22.1) 0.81 (0.49–1.35) 4.1 (25.9 to 14.1) .42
SGA* 26 (21.3) 33 (27.3) 0.78 (0.50–1.22) 6 (24.8 to 16.7) .28
Placental abruption 3 (2.5) 3 (2.5) 1 (0.21–4.86) 0 (23.9 to 3.9) 1
Perinatal death 1 (0.8) 4 (3.3) 0.25 (0.03–2.20) 2.5 (21.1 to 6) .37
Maternal death 0 0
Other secondary outcomes
Severe preeclampsia 16 (13.1) 17 (13.9) 0.94 (0.50–1.78) 0.8 (20.08 to 0.09) .85
Severe preeclampsia at
less than 34 wk of
gestation†
11 (9.0) 11 (9.0) 1.00 (0.45–2.22) 0 (27.2 to 7.2) 1
Preeclampsia .44
Antepartum 21 (17.2) 23 (18.9) 0.89 (0.52–2.15) 2.1 (27.7 to 12)
Postpartum 1 (0.8) 4 (3.3) 0.25 (0.03–2.15) 3.1 (21.3 to 7.4)
CONCLUSION
antepartum prophylactic enoxaparin does not significantly reduce placenta-
mediated complications in women receiving low-dose aspirin for previous severe
preeclampsia diagnosed before 34 weeks of gestation.
Ob Gyn VOL. 128, NO. 5, Nov. 2016
eparina

48.
Enoxaparin does not offer any preventative advantage
above low-dose aspirin even in women at high risk for
preeclampsia.
ISSHP 2018

49.
Take home messages
Identificazione della popolazione a rischio per preeclampsia:
Fattori materni
Velocimetria della circolazione uterina
Markers biochimici
markers diversi
Prevenzione nella popolazione a rischio:
acido acetilsalicilico
dosi: 100-150 mg/die
timing: entro la 16° settimana

50.
Grazie per l’attenzione
«Every maternal death is a tragedy for the woman and for her
family, and a loss to the community and society in which she lives»

51.
Use low-dose aspirin (preferably 150 mg/d) started before 16
weeks of pregnancy for women at increased risk for
preeclampsia, particularly if any of the following conditions
exist:
Previous preeclampsia
Preexisting medical conditions (including chronic hypertension,
underlying renal disease, or pregestational diabetes mellitus)
Antiphospholipid antibody syndrome
Multiple pregnancy
Obesity
Assisted reproduction pregnancy
ISSHP 2017
Enoxaparin does not offer any preventative
advantage above low dose aspirin even in
women at high risk for preeclampsia

52.
ISSHP supports first trimester screening for preeclampsia
when this can be integrated into the local health system
although the cost effectiveness of this approach remains to
be established.