Follow-up della Preeclampsia ed esiti a distanza - Sergio Ferrazzani

Follow-up della
preeclampsia e esiti a
distanza
sergio.ferrazzani@unicatt.it
Fondazione Policlinico Universitario A. Gemelli IRCCS
Università Cattolica del Sacro Cuore

Il futuro della donna:
Rischio cardiovascolare
• Dimensione del problema
– La preeclampsia è responsabile di circa il 20% delle morti materne
– Esiste un sensibile aumento del rischio cardiovascolare e
cerebrovascolare a distanza
ISSHP 2018

Patologie
renali
Patologie
Cardiovascolari
Ipertensione
Arteriosa
Alterazioni
funzionalità tiroidea
Patologie
oculistiche
Patologie del SNC
e “cognitive
impairment”

Cardiopatia ischemica dopo la preeclampsia
1 2 5 100.50.2
Relative risk
(random) (95% CI)
Relative risk
(random) (95% CI)
Total No of cases/
women who did not
have pre-eclampsia
Total No of cases/
women who had
pre-eclampsia
Hannaford 1997w8
Irgens 2001w15
Smith 2001w16
Wilson 2003w13
Kestenbaum 2003w14
Funai 2005w17
Ray 2005w18
Wirkstrom 2005w19
Total (95% CI)
Test for heterogeneity: χ2
=9.60, df=7, P=0.21, I 2
=27.1%
Test for overall effect: z=10.00, P=0.001
69/2371
27/24 155
12/22 781
26/1043
35/20 552
41/1070
228/36 982†
176/12 533
614/121 487
216/14 831
325/602 117
31/106 509
10/796
64/92 902
269/35 991
1262/950 885
2306/383 081
4483/2 187 112
Study
Ischaemic heart disease
1.65 (1.26 to 2.16)
3.61 (0.76 to 17.18)*
1.70 (0.86 to 3.35)
1.95 (0.90 to 4.22)
2.55 (1.70 to 3.83)†
3.01 (2.18 to 4.33)
2.10 (1.82 to 2.42)
2.21 (1.56 to 3.31)†
2.16 (1.86 to 2.52)
Increased
risk
Decreased
risk
Fig 1 | Pre-eclampsia and risk of fatal and non-fatal ischaemic heart disease events in later life. *Early and late pre-eclampsia
combined (see table 2 on bmj.com). †Mild and severe pre-eclampsia combined (see table 2 on bmj.com). ‡All maternal
placental syndromes
RESEARCH
Bellamy 2007

Relazione con la severità della patologia?
Bellamy 2007
mean number of years. The relative risk of
any cancer after pre-eclampsia was 0.96 (0
No evidence was found of heterogenei
I2
=43.2%; fig 6) or of small study bias
P=0.97).
Pre-eclampsia and risk of all cause mortality
Four studies (794 462 women) included
pre-eclampsia and 7537 women who later d
causesw13 w15-w17
(table 7). The average wei
follow-up was 14.5 years for each woma
who developed pre-eclampsia had an inc
of death from any cause compared with w
did not develop pre-eclampsia (1.49, 1.05 to
erogeneity was substantial (P<0.00001;
fig 7) and this was most noticeable betwee
early and late pre-eclampsia (P<0.00001;
Women developing pre-eclampsia before
gestation had a relative risk of 2.71 (1.99
death from any cause in later life com
women who had normal blood pressure
pregnancies.w15
No evidence of small stu
found (Egger test, P=0.84).
1 2 5 100.5
Relative risk of
future ischaemic
heart disease
(random) (95% CI)
Relative risk of
future ischaemic
heart disease
(random) (95% CI)
Parity
Primiparous: 6 studies (4502 cases)
Any pregnancy: 2 studies (595 cases)
Outcome severity
Fatal ischaemic heart disease: 4 studies (741 cases)
Combined (fatal and non-fatal) ischaemic heart disease:
4 studies (4356 cases)
Onset of disease
Early pre-eclampsia: 2 studies (50 cases)*
Severity of pre-eclampsia
Severe pre-eclampsia: 2 studies (2434 cases)
Mild pre-eclampsia: 2 studies (2517)
Overall relative risk
Group of studies
1.89 (1.40 to 2.55)
2.23 (1.21 to 4.09)
2.60 to (1.94 to 3.49)
2.17 (1.92 to 2.45)
7.71 (4.40 to 13.52)
2.86 (2.25 to 3.65)
1.92 (1.65 to 2.24)
2.16 (1.86 to 2.52)
Increased
risk
Decreased
risk
RES

Meta-analisi di 43 studi su donne con storia di Preeclampsia
Rischio di:
- Malattie Cardiovascolari
- Malattie Cerebrovascolari
- Ipertensione Arteriosa Cronica

Pregressa Preeclampsia:
Rischio di patologia cardiovascolare
Brown 2013

Rischio di patologia cerebrovascolare
Brown 2013

Rischio di ipertensione cronica
Brown 2013

ertensive disorder of pregnancy in their first
and 16 611 developed hypertension during
Women with a normotensive first pregnancy
s, 30s, or 40s had cumulative incidences of
on of 4.0%, 5.7%, and 11.3%, respectively, in
after delivery (fig 1, supplementary table 1).
ponding incidences for women whose first
wascomplicatedbyahypertensivedisorderof
were 13.7%, 20.3%, and 32.4%, respectively.
pattern was observed in the decade after a
egnancy in women with two pregnancies,
er pregnancy could have been complicated by
ve disorders of pregnancy (see supplementary
sks of post-pregnancy hypertension
uding women with cardiovascular disease
) or pregestational hypertension (n=20 249),
Time since first birth (years)
Cumulativeincidenceofhypertension(%)
0 1 2 3 4 5 6 7 8 9 10
0
20
30
40
10
40-49 years
No hypertensive
disorder
of pregnancy
Hypertensive
disorder
of pregnancy
30-39 years
95% CI
20-29 years
Fig 1 | Ten year cumulative incidences of hypertension by
BMJ:firstpublishedas10.1136/bmj.j3078on1
dic. ’19Follow-up della preeclampsia ed esiti a distanza 11
BMJ 2017;358:j3078
Danimarca
482.972 nullipare
(1995 - 2012)
Ipertese in gravidanza
Normotese in gravidanza

MACEs: Major Coronary
Events (fatal and non fatal)
2017
Proporzione di donne senza eventi coronari maggiori
Norvegia
506.350 donne

(1.32-fo
pre-ecla
Alto
fathers
had pre
term su
Overall
that in
fathers
death fr
who ha
occurre
amongNo of years from first birth
Survival(%ofmothers)
0 5 10 15 20 25
97
99
100
98
No pre-eclampsia and term delivery
No pre-eclampsia and preterm delivery
Pre-eclampsia and term delivery
Pre-eclampsia and preterm delivery
Long term mortality of mothers and fathers after
pre-eclampsia: population based cohort study
Henrik U Irgens, Lars Reisæter, Lorentz M Irgens, Rolv T Lie
Abstract
Objective To assess whether mothers and fathers
have a higher long term risk of death, particularly
from cardiovascular disease and cancer, after the
mother has had pre-eclampsia.
Design Population based cohort study of registry
data.
Subjects Mothers and fathers of all 626 272 births
that were the mothers’ first deliveries, recorded in the
Norwegian medical birth registry from 1967 to 1992.
Parents were divided into two cohorts based on
whether the mother had pre-eclampsia during the
pregnancy. Subjects were also stratified by whether the
birth was term or preterm, given that pre-eclampsia
might be more severe in preterm pregnancies.
Main outcome measures Total mortality and
mortality from cardiovascular causes, cancer, and
stroke from 1967 to 1992, from data from the
Norwegian registry of causes of death.
Results Women who had pre-eclampsia had a
1.2-fold higher long term risk of death (95%
confidence interval 1.02 to 1.37) than women who did
not have pre-eclampsia. The risk in women with
pre-eclampsia and a preterm delivery was 2.71-fold
higher (1.99 to 3.68) than in women who did not have
pre-eclamptic pregnancies than the fathers of
pregnancies in which pre-eclampsia did not occur.
Conclusions Genetic factors that increase the risk of
cardiovascular disease may also be linked to
pre-eclampsia. A possible genetic contribution from
fathers to the risk of pre-eclampsia was not reflected
in increased risks of death from cardiovascular causes
or cancer among fathers.
Introduction
Pre-eclampsia, which is characterised by hypertension
and proteinuria, occurs in 3-5% of pregnancies.1
The
condition may be life threatening to the mother and
the fetus if it is not properly managed, but it usually
ends when the baby and placenta are delivered.2
The causes of pre-eclampsia are not well under-
stood. A paradoxical preventive effect when the
mother smokes has been established, even though the
mechanism is unknown.3 4
Maternal and fetal genes,
including paternal genes expressed in the fetus,
probably also play a part.1 5
A high risk of recurrence of
pre-eclampsia in subsequent pregnancies supports the
role of an inherited susceptibility in the maternal
genes. In a previous study in Norwegian women we
reported a 12-fold increase in the risk of pre-eclampsia
in a second pregnancy when the woman had had pre-
Medical Birth
Registry of Norway,
Locus for Registry
Based
Epidemiology,
Department of
Public Health and
Primary Health
Care, University of
Bergen, Haukeland
Hospital, N5021
Bergen, Norway
Henrik U Irgens
medical student
Lars Reisæter
medical student
Lorentz M Irgens
professor
Rolv T Lie
professor
Correspondence to:
L M Irgens
lorentz.irgens@
mfr.uib.no
BMJ 2001;323:1213–7
significant) decreased risk of cancer. The long t
risk of death was no higher among the fathers
BMJ VOLUME 323 24 NOVEMBER 2001 bmj.com
Early
PE
Late
PE
Norvegia n=626.272

2012
OR
0
1,5
3
4,5
6
Num di gravidanze con PE
0 1 2 >2
Rischio cardiovascolare in più di una
gravidanza con PE
Norvegia n=836.147
Eccesso di mortalità CV nella PE da
nullipare
• problemi di salute che abbiano
scoraggiato o prevenuto
ulteriori gravidanze
• o PE stessa?

Rischio cardiovascolare dopo la PE:
Possibili meccanismi
Ø Infiammazione/Endoteliopatia/Aterosclerosi

Infiammazione/Endoteliopatia
/Aterosclerosi

Fisiopatologia e Fattori di Rischio
condivisi
Ipotesi
• La PE non causerebbe problemi futuri per la salute ma
condividerebbe molte caratteristiche fisiopatologiche con la
CVD
• A livello tissutale donne con PE e con CVD dimostrano
infiammazione e disfunzione endoteliale
• La disfunzione endoteliale può essere una condizione
preesistente nelle donne che svilupperanno la PE
Chen 2014, Libby 2015, Noori 2010
2019

Fisiopatologia e Fattori di Rischio condivisi
• La dilatazione flusso-
mediata (FMD)
dell’arteria brachiale
(test di disfunzione
endoteliale) risulta
alterata lungo tutta la
gravidanza di donne
con PE
Pohl 1986, Celermajer 1994, Noori 2010

Fisiopatologia e Fattori di Rischio condivisi
• Donne con PE continuano ad avere la dilatazione flusso-mediata
(FMD) dell’arteria brachiale alterata fino a 3 aa dopo la gravidanza
colpita
• Non correlazioni con:
– Obesità
– Ipertensione
– Insulino-resistenza
– Dislipidemia
– Iperomocisteinemia
– Caratteristiche del flusso brachiale
Chambers 2000-2001

Modificazioni longitudinali dell’insulino-sensibilità nella
gravidanza normale
2010

La PE si associa a un ambiente di
aumentata insulino-resistenza?

Insulino-resistenza & PE:
evidenze conflittuali
v Joffe AJOG 1998
v Kaaja Obstet Gynecol 1995
v Lorentzen Acta Obstet Gynecol Scand
1998
v Kaaja Metabolism 1999
v Roberts Br J Obstet Gynaecol 1998
v Caruso Hum Reprod 1999
v Bartha AJOG 2002
= Insulino-resistenzaInsulino-resistenza

Insulino-resistenza & PE:
evidenze conflittuali
Insulino-
resistenza
Autore Metodo Settimana del
parto
SI Kaaja 1999 Minimal model 38
SI Lorentzen 1998 OGTT 75 g >37
SI Joffe 1998 Minitest 50 g late
NO Roberts 1998 Minimal model >36
NO Caruso 1999 Glucose clamp 32
NO Bartha 2002 Short insulin
tolerance test
36

…dalla nostra esperienza:
studio preliminare
su 75 pz
STUDIO DELL’INSULINO-
RESISTENZA NELLE
GRAVIDANZE COMPLICATE DA
IPERTENSIONE

GH
N= 6
CH
N= 9
PE
N= 10
C
N= 10
p
Insulinemia
(µUI/ml)
media ± DS
15,2 ± 9,4 11,3 ± 4,7 8,0 ±4,0 7,0 ± 3,8 0,026
HOMA-IR 2,9 ± 2,1 2,1 ± 1,0 1,4 ± 0,7 1,2±0,9 0,059
QUICKI
index
0,34± 0,04 0,34±0,03 0,38 ±0,04 0,37±0,03 0,083
GH
N= 15
CH
N= 7
PE
N= 8
C
N= 10
p
Insulinemi
a (µUI/ml)
media ± DS
13,2 ±9,1 19,5 ±3,4 14,4 ±4,3 8,5 ±3,9 0,013
HOMA-IR 2,2 ± 1,5 3,5 ± 0,9 2,3 ± 1,0 1,5 ± 0,7 0,018
QUICKI
index
0,4 ± 0,04 0,32 ±0,01 0,34 ± 0,02 0,37±0,04 0,028
<34 settimane
≥34 settimane

Early PE
(n=10)
Late PE
(n=8)
Controls
(n=20)
Insulinemia
(µg/ml)
8,0 ± 4,0 14,4 ±4,3 7,7 ±3,8
HOMA-IR 1,4 ± 0,8 2,3 ± 1,0 1,35 ± 0,79
QUICKI index 0,38 ± 0,04 0,34 ± 0,02 0,37 ± 0,03
*
0
1
2
3
4
HOMA-IR
Early PE
Late PE
C
*
0,3
0,32
0,34
0,36
0,38
0,4
QUICKI index
Early PE
Late PE
C
Insulino resistenza nella Late PE
*
0
5
10
15
20
Insulinemia (µUI/ml )
Early PE
Late PE
C

(1.32-fo
pre-ecla
Alto
fathers
had pre
term su
Overall
that in
fathers
death fr
who ha
occurre
amongNo of years from first birth
Survival(%ofmothers)
0 5 10 15 20 25
97
99
100
98
No pre-eclampsia and term delivery
No pre-eclampsia and preterm delivery
Pre-eclampsia and term delivery
Pre-eclampsia and preterm delivery
Long term mortality of mothers and fathers after
pre-eclampsia: population based cohort study
Henrik U Irgens, Lars Reisæter, Lorentz M Irgens, Rolv T Lie
Abstract
Objective To assess whether mothers and fathers
have a higher long term risk of death, particularly
from cardiovascular disease and cancer, after the
mother has had pre-eclampsia.
Design Population based cohort study of registry
data.
Subjects Mothers and fathers of all 626 272 births
that were the mothers’ first deliveries, recorded in the
Norwegian medical birth registry from 1967 to 1992.
Parents were divided into two cohorts based on
whether the mother had pre-eclampsia during the
pregnancy. Subjects were also stratified by whether the
birth was term or preterm, given that pre-eclampsia
might be more severe in preterm pregnancies.
Main outcome measures Total mortality and
mortality from cardiovascular causes, cancer, and
stroke from 1967 to 1992, from data from the
Norwegian registry of causes of death.
Results Women who had pre-eclampsia had a
1.2-fold higher long term risk of death (95%
confidence interval 1.02 to 1.37) than women who did
not have pre-eclampsia. The risk in women with
pre-eclampsia and a preterm delivery was 2.71-fold
higher (1.99 to 3.68) than in women who did not have
pre-eclamptic pregnancies than the fathers of
pregnancies in which pre-eclampsia did not occur.
Conclusions Genetic factors that increase the risk of
cardiovascular disease may also be linked to
pre-eclampsia. A possible genetic contribution from
fathers to the risk of pre-eclampsia was not reflected
in increased risks of death from cardiovascular causes
or cancer among fathers.
Introduction
Pre-eclampsia, which is characterised by hypertension
and proteinuria, occurs in 3-5% of pregnancies.1
The
condition may be life threatening to the mother and
the fetus if it is not properly managed, but it usually
ends when the baby and placenta are delivered.2
The causes of pre-eclampsia are not well under-
stood. A paradoxical preventive effect when the
mother smokes has been established, even though the
mechanism is unknown.3 4
Maternal and fetal genes,
including paternal genes expressed in the fetus,
probably also play a part.1 5
A high risk of recurrence of
pre-eclampsia in subsequent pregnancies supports the
role of an inherited susceptibility in the maternal
genes. In a previous study in Norwegian women we
reported a 12-fold increase in the risk of pre-eclampsia
in a second pregnancy when the woman had had pre-
Medical Birth
Registry of Norway,
Locus for Registry
Based
Epidemiology,
Department of
Public Health and
Primary Health
Care, University of
Bergen, Haukeland
Hospital, N5021
Bergen, Norway
Henrik U Irgens
medical student
Lars Reisæter
medical student
Lorentz M Irgens
professor
Rolv T Lie
professor
Correspondence to:
L M Irgens
lorentz.irgens@
mfr.uib.no
BMJ 2001;323:1213–7
significant) decreased risk of cancer. The long t
risk of death was no higher among the fathers
BMJ VOLUME 323 24 NOVEMBER 2001 bmj.com
Early
PE
Late
PE
n=626.272

Possibili spiegazioni…
• … forse la curva di mortalità materna a lungo
termine della Norvegia potrebbe non essere
adattabile a quella dell’Italia
• o la mortalità cardiovascolare potrebbe non
correlarsi affatto con l’insulino-resistenza
(sindrome metabolica)

Quesiti…
• Forse c’è altro?

cytokeratin fra
cause for incre
Endothelial
been attribut
excess produ
species (77). A
produced by
(NO) synthe
methyl-ester)
hypertension
(110). In preec
of enzymatic
high oxidative
tic placentas (
tion (89, 104)
(101), and pro
(101). There h
looking for be
a small study,
was also found
Unfortunately
plementation
has not been s
in nulliparous
and other adv
mary, althou
preeclampsia,
test specific an
secretion of to
mote vascular
Genetics. A
occur in wome
of preeclamps
woman’s risk
(16). If a wom
already father
ent woman, h
almost double
paternal (thus
position and s
that requires
gene in both
hypothesized
has been exte
ings about its
Still others bel
influence from
increase both sFlt1 and sEng in pregnant mice (112).
The effects of these antibodies can be blocked with
losartan, a pharmacological AT1 receptor antagonist,
or by an antibody-neutralizing peptide (30). However,
AT1 receptor autoantibodies do not give explanation
for the suppression of aldosterone production noted
in preeclampsia (42). Present not only during preg-
nancy, AT1 receptor autoantibodies appear to be
increased as well in malignant renovascular hyperten-
sion and vascular rejection (30). These autoantibodies
may account for the increased angiotensin II sensitiv-
ity for preeclampsia. In summary, AT1-AA may be one
of several insults that can contribute to the placental
damage that is proximally linked to the production of
anti-angiogenic factors (see FIGURE 4).
Immunological intolerance and inflamma-
tion/oxidative stress. Immune maladaption remains
an intriguing explanation about the pathogenesis of
preeclampsia. Normal placentation requires the
development of immune tolerance between the fetus
and the mother. Preeclampsia occurs more often in
first pregnancies, after a change in paternity (94), or
with long interpregnancy interval (95). In addition,
women using barrier contraceptive methods that
reduce maternal exposure to sperm have increased
incidence of preeclampsia (46). Women who con-
ceived via intracytoplasmic sperm injection (ICSI) in
which sperm was surgically obtained from the male
had a threefold increased risk of preeclampsia com-
pared with ICSI cases where sperm was obtained by
ejaculation (102). These observations suggest that
preeclampsia may involve an abnormal maternal
immune response to novel paternally derived fetal
antigens. Women with untreated HIV have a very low
incidence of preeclampsia, but the incidence returns
to normal in HIV-positive women who are on anti-
retroviral therapy (108).
Natural killer (NK) cells at the maternal/fetal inter-
face are also thought to play an important role in the
pathogenesis of preeclampsia. They are thought to be
important in modulating immune tolerance required
for normal placental development as well as the
induction of angiogenic factors and vascular remodel-
ing (33). Recent genetic studies have suggested that
the susceptibility to preeclampsia may be influenced
by polymorphic human leukocyte antigen C (HLA-C)
ligands and the killer immunoglobulin receptors
154 PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org
preeclampsia have increased vascular responsiveness
to angiotensin II and other vasoconstrictive agents.
Angiotensin II is a well recognized octapeptide medi-
ator of elevated blood pressure that signals arterial
vasoconstriction after binding to the angiotensin II
type 1 (AT1) receptor. Angiotensin II hypersensitivity
in preeclampsia may also be due to heterodimeriza-
tion of AT1 receptors with bradykinin receptors (1).
FIGURE 4. Summary of the pathogenesis of preeclampsia
Immune factors (such as AT1-AA), oxidative stress, NK cell abnormalities, and other fac-
tors may cause placental dysfunction, which in turn leads to the release of anti-angio-
genic factors (such as sFlt1 and sEng) and other inflammatory mediators to induce
hypertension, proteinuria, and other complications of preeclampsia.
byguestonNovember4,2016http://physiologyonline.physiology.org/Downloadedfrom
Studies have identified agonistic (AT1) rec
autoantibodies in women with preeclampsia
These AT1 receptor autoantibodies, like angioten
itself, could lead to the production of tissue fact
endothelial cells. Xia et al. found that AT1 rec
autoantibodies decreased invasiveness of imm
ized human trophoblasts in an in vitro inv
assay(109). Studies from Zhou et al. indicate tha
receptor autoantibodies recovered from the cir
tion of women with preeclampsia can replicate th
features of preeclampsia in pregnant mice
increase both sFlt1 and sEng in pregnant mice
The effects of these antibodies can be blocked
losartan, a pharmacological AT1 receptor antag
or by an antibody-neutralizing peptide (30). How
AT1 receptor autoantibodies do not give explan
for the suppression of aldosterone production n
in preeclampsia (42). Present not only during
nancy, AT1 receptor autoantibodies appear
increased as well in malignant renovascular hype
sion and vascular rejection (30). These autoantib
may account for the increased angiotensin II sen
ity for preeclampsia. In summary, AT1-AA may b
of several insults that can contribute to the plac
damage that is proximally linked to the producti
Immunological intolerance and inflam
tion/oxidative stress. Immune maladaption rem
an intriguing explanation about the pathogene
preeclampsia. Normal placentation requires
development of immune tolerance between the
and the mother. Preeclampsia occurs more oft
first pregnancies, after a change in paternity (9
with long interpregnancy interval (95). In add
women using barrier contraceptive methods
reduce maternal exposure to sperm have incr
incidence of preeclampsia (46). Women who
ceived via intracytoplasmic sperm injection (IC
which sperm was surgically obtained from the
had a threefold increased risk of preeclampsia
pared with ICSI cases where sperm was obtain
ejaculation (102). These observations suggest
preeclampsia may involve an abnormal mat
immune response to novel paternally derived
antigens. Women with untreated HIV have a ver
incidence of preeclampsia, but the incidence re
to normal in HIV-positive women who are on
Natural killer (NK) cells at the maternal/fetal
face are also thought to play an important role i
pathogenesis of preeclampsia. They are thought
important in modulating immune tolerance req
for normal placental development as well a
induction of angiogenic factors and vascular rem
ing (33). Recent genetic studies have suggested
the susceptibility to preeclampsia may be influe
by polymorphic human leukocyte antigen C (HL
ligands and the killer immunoglobulin rece
clearly critical to successfully supporting a pregnancy,
but overt placental ischemia and hypoxia may not be
the causative factor in preeclampsia but rather an
important secondary event.
Renin-angiotensin-aldosterone. In addition to
altered angiogenic balance and failed cytotrophoblast
invasion, the renin-angiotensin-aldosterone axis is
also perturbed in preeclampsia. In normal pregnancy,
renin, aldosterosterone, and angiotensin are
increased. These hormones are suppressed relative to
normal pregnancy in preeclampsia. Women with
preeclampsia have increased vascular responsiveness
to angiotensin II and other vasoconstrictive agents.
losartan, a pharmacological AT1 receptor ant
or by an antibody-neutralizing peptide (30). H
AT1 receptor autoantibodies do not give exp
for the suppression of aldosterone productio
in preeclampsia (42). Present not only durin
nancy, AT1 receptor autoantibodies appea
increased as well in malignant renovascular hy
sion and vascular rejection (30). These autoan
may account for the increased angiotensin II
ity for preeclampsia. In summary, AT1-AA ma
of several insults that can contribute to the p
damage that is proximally linked to the produ
Immunological intolerance and infl
tion/oxidative stress. Immune maladaption
an intriguing explanation about the pathoge
preeclampsia. Normal placentation requi
development of immune tolerance between t
and the mother. Preeclampsia occurs more
first pregnancies, after a change in paternity
with long interpregnancy interval (95). In a
women using barrier contraceptive metho
reduce maternal exposure to sperm have in
incidence of preeclampsia (46). Women w
ceived via intracytoplasmic sperm injection (
which sperm was surgically obtained from t
had a threefold increased risk of preeclamps
pared with ICSI cases where sperm was obta
ejaculation (102). These observations sugg
preeclampsia may involve an abnormal m
immune response to novel paternally deriv
antigens. Women with untreated HIV have a v
incidence of preeclampsia, but the incidence
to normal in HIV-positive women who are
Natural killer (NK) cells at the maternal/fet
face are also thought to play an important ro
pathogenesis of preeclampsia. They are thoug
important in modulating immune tolerance r
for normal placental development as well
induction of angiogenic factors and vascular r
ing (33). Recent genetic studies have sugges
the susceptibility to preeclampsia may be inf
by polymorphic human leukocyte antigen C (
ligands and the killer immunoglobulin re
154 PHYSIOLOGY • Volume 24 • June 2009 • www.physiologyonline.org
Nuova visione

Remodelling cardiaco
Pregnancy duration (weeks)
Increase(%)
LVM
LVDD
LVSD
EF

Rimodellamento cardiaco
• Massa del LV
– Atleta in allenamento (dopo 2 aa) +25%
– Gravidanza (38 settimane) +40%
2016

Le origini delle complicanze della gravidanza
• Tutti i sistemi organici devono lavorare al massimo
• Le complicanze compaiono quando richieste superano offerta
• L’invecchiamento dei sistemi organici riduce le riserve
conducendo a una ricorrenza dei sintomi anni più tardi

This U-shape
1
1.1
1.2
1.3
1.4
1.5
1.6
1 2 3 4 5 6 7 8 9
Number of Children
Predicted
hazardfuction
Fig. 1. Association between number of children (N) and total mortality in mothers: A
Table 5
Joint association betw
Characteristic
No. of children M
1e4 <
1e4
5+
5+
* HR estimates der
y
Adjusted for mot
diabetes mellitus, ge
multiple pregnancies
U.P. Dior et al. / Annals of Epidemiology 23 (2013) 13e16
Association between number of children and mortality of mothers: results
of a 37-year follow-up study
Uri P. Dior MD, MPH a,b,*,1
, Hagit Hochner PhD a,1
, Yechiel Friedlander PhD a
,
Ronit Calderon-Margalit MD, MPH a
, Dena Jaffe PhD a
, Ayala Burger MSc a
, Meytal Avgil PhD a
,
Orly Manor PhD a
, Uriel Elchalal MD b
a
Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
b
Department of Obstetrics and Gynecology, Hadassah Medical Center and Hebrew University-Hadassah Medical School, Jerusalem, Israel
a r t i c l e i n f o
Article history:
Received 26 April 2012
Accepted 26 October 2012
Available online 22 November 2012
Keywords:
Parity
Mothers’ mortality
Socioeconomic factors
Survival
a b s t r a c t
Purpose: To examine the association between parity and long-term, all-cause mortality and mortality
owing to specific causes in women.
Methods: This prospective population-based study included 40,454 mothers who gave birth in Western
Jerusalem, Israel, to 125,842 children and were followed for an average of 37 years after the birth of their
first child. Cox proportional hazards models were used to evaluate long-term total and specific-cause
mortality of women by their parity.
Results: We found a U-shaped relationship between the number of offspring and risk of all-cause
mortality in mothers. After adjustment for sociodemographic characteristics and maternal health and
obstetric conditions, higher mortality rates were observed for mothers of 1 child (hazard ratio [HR], 1.18;
95% confidence interval [CI], 1.04e1.4), mothers of 5 to 9 children (HR, 1.21; 95% CI, 1.09e1.33), and
mothers of 10 or more children (HR, 1.49; 95% CI, 1.12e1.99) compared with mothers of 2 to 4 children.
Mortality risk from specific causes including coronary disease, circulatory disease, and cancer were
increased for multiparous women.
Conclusions: In this long-term follow-up study, there was an association between number of children and
mortality risk for mothers. These findings suggest that maternal pregnancies and postnatal character-
istics as reflected by number of children may have consequences for long-term maternal health.
Ó 2013 Elsevier Inc. All rights reserved.
The reproductive patterns of women have long-term implica-
tions for women’s health, yet only a few studies have addressed the
association between parity, as reflected by number of children, and
long-term mortality. Theories from evolutionary biology, such as the
“disposable soma” theory, suggest a trade-off between reproductive
factors and somatic maintenance [1,2]. These theories are based
both on experiments in Drosophila melanogaster and on epidemio-
logic studies that show a positive relationship between fertility and
mortality [3,4]. The physiologic findings complement the antago-
nistic pleiotropy theory, which suggests that deleterious mutations
that accumulate during an organism’s lifetime, favor reproduction at
younger ages but are harmful at later ages [5,6].
Findings from studies that have investigated historical cohorts
as well as contemporary populations have been inconsistent.
Although most of these studies showed a positive association
between parity and mortality [7e11], others found the opposite
association [12e14]. It may be that this inconsistency can to some
extent be attributed to short follow-up period, loss to follow-up,
misclassification of the number of births (especially in historical
cohorts), random error owing to small numbers at the extremes of
family size, small differences in mortality risk, and failure to adjust
for important potential confounders such as biological and socio-
economic factors [15].
The purpose of the current study was to examine the associa-
tions between number of children and all-cause mortality and
mortality owing to specific causes in mothers after taking into
account maternal health conditions as well as lifestyle and socio-
economic factors as potential confounders.
Methods
The Jerusalem Perinatal Study (JPS), a population-based cohort,
recorded data on 44,067 mothers with a total of 92,408 births in all
* Corresponding author. Department of Obstetrics and Gynecology, Hadassah
Medical Center and Hebrew University-Hadassah Medical School, P.O. Box 12000,
Jerusalem 91120, Israel. Tel.: 972-50-5172642; fax: 972-77-3355207.
E-mail address: uri.dior@gmail.com (U.P. Dior).
1
First and second authors contributed equally to this study.
Contents lists available at SciVerse ScienceDirect
Annals of Epidemiology
journal homepage: www.annalsofepidemiology.org
1047-2797/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved.
2013

Fase preclinica Fase manifesta Anni dopo…
Rimodellamento
concentrico e
ipertrofia concentrica LV
Danno sub-
endocardico precoce?!
Deficit di contrattilità
Lavoro cardiaco al
limite della propria
riserva
Valensise 2001, Valensise 2008, Bijnens 2009, Novelli 2012, Melchiorre 2013, Lykke 2009,
Mongraw-Chaffin 2010
Rischio più elevato di
ipertensione cronica,
scompenso cardiaco e
cardiopatia ischemica
rispetto a gravide
normali o late PE
Rischio cardiovascolare della early PE:
il ruolo dell’emodinamica

Scompenso cardiaco Stadio B nella PE
un anno postpartum
0%
10%
20%
30%
40%
50%
60%
70%
80%
Early PE Late PE Controls
*p0.05 Early PE
vs
Late PE and Controls
*
Melchiorre 2011

Donne con early PE
• Soggette a remodelling/ipertrofia del LV
• Maggiormente predisposte alla PE e al danno cardio-vascolare
a lungo termine…
• … a prescindere dalla loro insulino-resistenza in gravidanza

A complemento della
patologia cardiovascolare

• Donne con PE e Eclampsia
- scarsi segni di deficit
neurocognitivo
- solo lievi ritardi nella velocità
del movimento
• Presenti però deficit cognitivi da
disfunzioni più complesse in
situazioni di stress della vita
quotidiana come ansietà e
depressione
• 45 Eclampsia
• 51 PE
• 48 Controlli
a 6-8 aa dal parto

Patologia del SNC e “cognitive impairment”
40 donne con storia di PE vs 40 donne con storia di gravidanza normotesa
Valutazione neurologica ad una distanza media di 35 anni dal parto
2017

Il “Mild cognitive impairment” è
più frequente nelle donne dopo
una PE
Le abilità più frequentemente
interessate sono quelle a carico di
funzioni esecutive, verbali ed
attenzione.
AuthorManuscriptAuthorManuscript
Table 4
Consensus-based assessment of cognitive status
Variable
Normotensive
(n=40) N (%)
Preeclampsia
(n=40) N (%) P-value
Cognitive Impairment 0.03~
None 37 (93%) 32 (80%)
MCI-single domain 2 (5%) 0 (0%)
MCI-multiple domains 1 (3%) 7 (18%)
Dementia 0 (0%) 1 (3%)
Number of Domains Affected 0.03~
0 37 (93%) 32 (80%)
1 2 (5%) 0 (0%)
2 1 (3%) 5 (13%)
3 0 (0%) 1 (3%)
4 0 (0%) 2 (5%)
MCI/Dementia 0.10
No 37 (93%) 32 (80%)
Yes 3 (8%) 8 (20%)
~
Measure of impairment analyzed as an ordinal variable with the Cochran-Armitage trend test.
MCI = mild cognitive impairment.
Fields 2017

34 donne con storia di PE vs 49 donne con storia di gravidanza normotesa
Valutazione con RM encefalo ad una distanza di 5-15 anni dal parto
Siepmann Neurology® 2017

• PE
• modificazioni della sostanza bianca del lobo temporale
• ridotto volume corticale.
• Gravità proporzionale alla distanza dal parto come per continuo
accumulo di danno dopo la gravidanza

Insufficienza renale
Da 34.581 parti
44 donne con diagnosi di “End-Stage Renal Disease” vs 88 controlli
2017

Kattah 2017
PE 4 volte più frequente nei casi di
insufficienza renale

Kattah 2017
- Malattia renale subclinica preesistente
(21% vs 1%)
- Podocituria importante anche dopo il
parto
- Fattori di rischio cardiovascolari dopo la
preeclampsia (ipertensione cronica)
PE 4 volte più frequente nei casi di insufficienza renale

Altre segnalazioni della letteratura
Alterazione della funzionalità tiroidea: maggiore rischio
di ipotiroidismo non autoimmune
Probabile meccanismo:
-Danno ischemico tiroideo
- Esposizione a fattori anti-angiogenetici
Rischio di cataratta (RR totale=1.21, RR per preeclampsia
precoce=1.52, RR per preeclampsia tardiva=1.17)
Probabili meccanismi:
-Danno ossidativo
- Condivisione fattori di rischio

Raccomandazioni profilattiche
Storia di preeclampsia = fattore di rischio maggiore» come
- Ipertensione
- Ipercolesterolemia
- Fumo
- Inattività fisica
- Obesità
CVD 1% nel basso rischio vs 19 % nell’alto rischio
Raccomandazioni
- Stop al fumo
- Attività fisica
- Riduzione del peso in donne obese o sovrappeso mediante una dieta
“DASH-like”
Nella preeclampsia pretermine o ricorrente
Raccomandazioni Aggiuntive
- Controllo annuale della pressione arteriosa
- Controllo annuale dell’assetto glucidico, lipidico
2014

• Donne con GH, CH e PE follow-up a lungo termine per il
rischio CV
• Rendere noti i rischi di malattia CV, stroke, diabete, VTE, e
malattia renale cronica
• Rischio di ricorrenza della PE del 15% + di GH del 15%. ASA
per profilassi
• Rischio di SGA nelle gravidanze successive a GH e PE
• Regolare follow-up per monitorare PA, assetto lipidico e
glicemia
• Adottare stile di vita con mantenimento del peso ideale e
regolare esercizio aerobico
ISSHP 2018

Infarto miocardico: differenze di genere
🧔 Uomini ostruzione delle arterie maggiori cardiache con lesioni
arteriosclerotiche e placche a maggior tendenza alla rottura
Donne erosione delle placche che espone il tessuto
sottostante attivando la formazione di coaguli
• Spesso lesioni microvascolari raramente visualizzabili alla
coronarografia
Sharaf 2001, Pepine 2010

Peculiarità delle donne
• Patologia del microcircolo difficile da rilevare
• Mortalità da infarto miocardico, da angioplastica e da
applicazione di by-pass più elevata nelle donne
• Donne palesemente sotto-valutate e sotto-trattate anche se
appartenenti a categorie a alto rischio
Mehta 2016, National Institutes of Health: National Heart, Blood and Lung Institute. The heart truth

Riduzione del rischio e follow-up
• Modificazione dello stile di vita (esercizio regolare e dieta)
nelle donne con pregressa PE può condurre a ↓ 4-13% rischio
di CVD
Berks 2013
2019

Dietary Approaches to Stop Hypertension
Prevede un'alimentazione povera di sale, grassi saturi, colesterolo e ricca
di K, Mg, vitamina D ed E, proteine vegetali, omega 3 e fibre

Consulenza preconcezionale
• Adeguata prevenzione primaria
– terapie comportamentali
– raggiungimento di un BMI pregravidico adeguato

Rivalutazione a 6-12 mesi dal parto delle donne con preeclampsia
Ø Anamnesi familiare
Ø Anamnesi personale (stile di vita, attività fisica, tabagismo, abuso di
sostanze)
Ø Controllo della Pressione Arteriosa
Ø Misurazione di peso, altezza e BMI; misurazione della circonferenza
addominale
ØAssetto lipidico e glucidico (trigliceridi, colesterolo totale, colesterolo
LDL, colesterolo HDL, curva glicemica, emoglobina glicata)
Ø Valutazione indici di funzionalità renale
Ø Studio delle trombofilie congenite ed acquisite

Profilassi/Terapia farmacologica
ØIpertensione: Pressione arteriosa 140/90mmHg o 130/80mmHg in
pazienti con comorbilità come insufficienza renale cronica o diabete mellito.
(Livello di evidenza A)
ØDislipidemia: la somministrazione di statine (Livello di evidenza B)
andrebbe valutata in caso di:
ØColesterolo LDL 100mg/dL e donne ad alto rischio
ØColesterolo LD L130mg/dL e donne a rischio moderato
ØColesterolo LDL 160mg/dL e donne a rischio basso
ØValutazione Profilassi con Aspirina in donne “a rischio” sopra i 65 anni,
oppure donne con fattori di rischio addizionali per stroke (terapie
estroprogestiniche, fibrillazione atriale, obesità, sindrome metabolica,
emicrania con aura), anche sotto i 65 anni.

Calcolo del rischio cardiovascolare

Il futuro del bambino nato da madre
ipertesa
-Patologia di crescita
fetale
-Rischio cardiovascolare
e metabolico
IPERTENSIONEMATERNA

I neonati da madre preeclamptica, specie se in epoca gestazionale precoce, hanno valori di peso e
di percentile di peso mediamente più bassi rispetto ai neonati nati da madre con ipertensione
gestazionale e da madre normotesa
Crescita fetale nei disordini
ipertensivi della gravidanza
2011

Crescita fetale nei disordini
ipertensivi della gravidanza
Dati UCSC
2017

Controlli Ipertensione
gestazionale
Preeclampsia
Peso del 1° gemello (g) 2435±596 2470±409 2322±645
Peso del 2° gemello (g) 2385±620 2450±578 2133±739
SGA twin 1 n (%) 127 (14%) 30 (15,3%) 24 (31.6%)
SGA twin 2 n (%) 188 (20,7%) 41 (20,9%) 37 (48.7%)
Lo stesso comportamento si osserva nelle gravidanze gemellari, nelle
quali addirittura l’ipertensione gestazionale sembra avere un ruolo
benefico per la crescita fetale
2000
2015

Il futuro del neonato da madre preeclamptica
Rischio Fattore di rischio
Bassa statura, elevato BMI Insufficenza placentare
Intolleranza glucidica / Diabete / Insulino resistenza Insufficienza placentare
Ipertensione Suscettibilità ormonale, BMI elevato
Rischio cerebrovascolare Brain sparing
Rimodellamento del circolo cerebrale
Displasia broncopolmonare Fattori anti-angiogenici
Problemi neuro-cognitivi Insufficienza placentare
Iperandrogenismo, PCO Insufficienza placentare
Ospedalizzazione Endocrinopatie, infezioni, problemi nutrizionali, malattie
del sistema emopoietico, digerente e respiratorio
De Carolis, Aggiornamento medico, 2011

Il futuro del neonato IUGR:
Rischio metabolico e cardiovascolare
Mcmillen, Physiological Reviews, 2005

Il futuro del nato IUGR:
Complicanze a lungo termine
Sindrome
Metabolica
Patologie
Cardiovascolar
i
Ipertensione
Arteriosa
Obesità
Diabete tipo II
Alterazione della
funzionalità renale
Alterazione della
funzionalità
polmonare
Sequele
neuropsicologiche
Osteoporosi

Obesità, gravidanza e sindrome
metabolica nel nascituro:
Un circolo vizioso?

C’è un significativo aumento del rischio di morte per patologia
cardiovascolare nelle donne con
Preeclampsia + Parto Pretermine BMJ
2001

ruolo dell’Insulino-resistenza
La gravidanza fisiologica porta ad una condizione transitoria di
insulino-resistenza, specie negli ultimi due trimestri…

…alla patologia
Questo processo diviene più enfatizzato
nelle donne con ipertensione gestazionale
e con preeclampsia “tardiva”, al contrario
della preeclampsia precoce
Kaaja et al. 1999
PREECLAMPSIA
TARDIVA
PREECLAMPSIAPRECOCE
IPERTENSIONEGESTAZIONALE
1999

2012
OR
0
1,5
3
4,5
6
Num di gravidanze con PE
0 1 2 2
Rischio cardiovascolare in più di una
gravidanza con PE
N=836.147

Possibili meccanismi
Ø Infiammazione/Endoteliopatia/Aterosclerosi. Sia nella preeclampsia a sia
nell’aterosclerosi, infatti, il primum movens è uno stato infiammatorio con attivazione dei
monociti/macrofagi. Tale processo è agevolato da una endoteliopatia dovuta a specie
reattive dell’ossigeno e particelle endotelio-tossiche che favoriscono l’emissione endoteliale
di chemochine, citochine e molecole di adesione che portano all’invasione leucocitaria del
tessuto endoteliale e dell’infiammazione.
Ø Insulino-resistenza/Sindrome metabolica. Studi sull’utilizzo del minimal model e del clamp
euglicemico-iperinsulinemico hanno dimostrato una enfatizzazione della fisiologica insulino-
resistenza della gravidanza nelle pazienti con ipertensione gestazionale e la preeclampsia
tardiva o “maternogenica”.
Ø Disfunzione cardiaca. Nelle donne con preeclampsia ricorrente sono stati osservati segni di
disfunzione diastolica e diverse anomalie del ventricolo sinistro, che persistono anche fuori
gravidanza, mentre nelle donne con preeclampsia episodica non ricorrente mostrano
caratteristiche strutturali e funzionali del ventricolo sinistro intermedie, rispetto alla
popolazione generale e alle donne con preeclampsia ricorrente.

…ovunque esiste un cut-off
netto tra PE precoce e tardiva?

0
500
1000
1500
2000
2500
3000
3500
4000
4500
25 27 29 31 33 35 37 39 41 43
Serie1
54 52
70 65
31 29
0
50
26-28 29-31 32-34 35-37 38-40 41-42
%iposviluppo
PE
n=352

Early e late PE in Italia
• PE precoce e tardiva
• PE placentare e materna
prescindono dalla
settimana di gestazione

Conclusioni
• In Italia una sottopopolazione di PE meno frequente…
• … ma più grave perché associata a maggior frequenza di
insufficienza placentare e quindi di FGR
• Il rischio vascolare a distanza negli anni rilevato in alcuni paesi
industrializzati potrebbe non essere rappresentativo della
nostra popolazione
• L’insulino-resistenza non si associa alla PE placentare e
potrebbe quindi non essere la causa della prognosi
cardiovascolare avversa nel follow-up della donna

KAAJA ET AL
curve during the first 10 minutes) multiplied by
RESULTS
control women had a similar blood glucose
al glucose tolerance test, but the insulin
mptic women was significantly higher (Fig
the insulin curve in preeclamptic women
L • min) was 59% larger (P = .001) than in
(5,157 _+ 611 ~tU/mL • rain). In contrast to
nsulin levels, fasting C-peptide levels in
en (0.73- 0.04 nmol/L) were higher
ontrol women (0.58 _+ 0.05 nmol/L). The
ratio showed no difference between the two
insulin sensitivity was 0.26 × 10.4.
.52 × 10-4- mill-1 • ~U/mL in preeclamp-
45 × 10.4. min -1. tJU/mL to 3.62 ×
L in controls. As a mean value, insulin
lower (P = .009) in preeclamptic women
Fig 2). The first 10-minute insulin response,
rea under the curve, was 53% higher in
n (971.0 +_ 81.6 pU/mL • rain) than in con-
_+ 61.5 ~U/mL • min, P = .004). The dispo-
t differ between preeclamptic women and
008 v 0.098 ,+ 0.010, P = .48).
er delivery, insulin sensitivity was increased
lamptic women (from 1.11 ,+ 0.15 to
. rain-1 • pU/mL, P = .0001) and 3.8-fold
7 ,+ 0.19 to 6.86 +_0.79 × 10.4. min-1 -I.IU/
t postpartum insulin sensitivity was reduced
ptic group compared with the control group
he disposition index did not differ between
preeclampsia and controls (0.168-+ 0.025 v
62). NO significant correlations emerged be-
vity during pregnancy and after delivery in the
y correlated negatively with the weeks of
mptic women (r = -.53, P = .01), but not
3, P = .64). The insulin response to oral
n sensitivity in the intravenous glucose
d a strong negative correlation in preeclamp-
0, P = .0004), but not in control women
. Furthermore, insulin sensitivity correlated
seline C-peptide concentrations both in
n (r =-.62; P = .002) and in control
P = .02) (Fig 3).
evels were higher in preeclamptic women
/L, P = .0001) than in control women
L). In the whole study population, insulin
ively related to the uric acid level (r = -.35;
women, serum triglycerides were 37%
A
Q e~
1~ l-
e, 'e,,
:~ .-
w=,tE
p=0.009
2- I I
//Preeclamptic Control
women women
During pregnancy
B
t/l.,T
ul
8-
7'
6-
4-
3-
2-
1J
p=0.04
I I
Preeclamptic Control
women women
After delivery
Fig 2. Insulin sensitivity in intravenous glucose tolerance as-
sessed by minimal model analysis in women with preeclampsia and
normotensive control women (A) during pregnancy and (B) 12 weeks
after delivery. Data are the mean -+ SE,
were 70% higher in preeclamptic women (0.17 -+ 0.01 g/L)
KAAJA ET AL
ulin curve during the first 10 minutes) multiplied by
RESULTS
and control women had a similar blood glucose
oral glucose tolerance test, but the insulin
clamptic women was significantly higher (Fig
der the insulin curve in preeclamptic women
U/mL • min) was 59% larger (P = .001) than in
en (5,157 _+ 611 ~tU/mL • rain). In contrast to
al insulin levels, fasting C-peptide levels in
omen (0.73- 0.04 nmol/L) were higher
n control women (0.58 _+ 0.05 nmol/L). The
lin ratio showed no difference between the two
f insulin sensitivity was 0.26 × 10.4.
o 2.52 × 10-4- mill-1 • ~U/mL in preeclamp-
0.45 × 10.4. min -1. tJU/mL to 3.62 ×
U/mL in controls. As a mean value, insulin
37% lower (P = .009) in preeclamptic women
ls (Fig 2). The first 10-minute insulin response,
e area under the curve, was 53% higher in
men (971.0 +_ 81.6 pU/mL • rain) than in con-
.8 _+ 61.5 ~U/mL • min, P = .004). The dispo-
not differ between preeclamptic women and
+ 0.008 v 0.098 ,+ 0.010, P = .48).
after delivery, insulin sensitivity was increased
eeclamptic women (from 1.11 ,+ 0.15 to
0-4. rain-1 • pU/mL, P = .0001) and 3.8-fold
1.77 ,+ 0.19 to 6.86 +_0.79 × 10.4. min-1 -I.IU/
Yet postpartum insulin sensitivity was reduced
lamptic group compared with the control group
. The disposition index did not differ between
or preeclampsia and controls (0.168-+ 0.025 v
= .62). NO significant correlations emerged be-
sitivity during pregnancy and after delivery in the
vity correlated negatively with the weeks of
clamptic women (r = -.53, P = .01), but not
-.13, P = .64). The insulin response to oral
ulin sensitivity in the intravenous glucose
wed a strong negative correlation in preeclamp-
-.70, P = .0004), but not in control women
10). Furthermore, insulin sensitivity correlated
baseline C-peptide concentrations both in
omen (r =-.62; P = .002) and in control
8, P = .02) (Fig 3).
id levels were higher in preeclamptic women
mol/L, P = .0001) than in control women
ool/L). In the whole study population, insulin
gatively related to the uric acid level (r = -.35;
A
Q e~
1~ l-
e, 'e,,
:~ .-
w=,tE
p=0.009
2- I I
//Preeclamptic Control
women women
During pregnancy
B
t/l.,T
ul
8-
7'
6-
4-
3-
2-
1J
p=0.04
I I
Preeclamptic Control
women women
After delivery
Fig 2. Insulin sensitivity in intravenous glucose tolerance as-
sessed by minimal model analysis in women with preeclampsia and
normotensive control women (A) during pregnancy and (B) 12 weeks
after delivery. Data are the mean -+ SE,
dell’insulino-resistenza in
condizioni patologiche
come la Late PE e la GH
Kaaja et al. 1999
LatePE
EarlyPE

Due importanti teorie
The disposable soma
• A causa delle richieste competitive
della riproduzione si investe di meno
nel mantenimento dei tessuti somatici
di quanto non sia necessario per una
lunga sopravvivenza
The antagonistic pleiotropy
• Cer~ alleli che sono favori~ in
conseguenza di un effe€o benefico
precoce (fer~lità e crescita della prole)
presentano anche effe‚ deleteri
tardivi

Differenti tipi di PE in alcuni paesi
industrializzati
• Possono spiegare differenze nell’epidemiologia della mortalità
cardiovascolare materna
• La curva di mortalità materna a lungo termine delineata in
Norvegia potrebbe non essere adattabile a quella in Italia

Malattia cardiovascolare (CVD)
• Tra 20 aa e 49 aa la frequenza di insulino-resistenza nella
donna raggiunge il 20%
• Molte meno donne sviluppano la PE
• È solo l’insulino-resistenza causa di danno CVD?
• Forse c’è altro….

Risk factors for cardiovascular disease
Risk factor Risk Ratio (95% C.I.) CVD
PCOS 1.38 (1.34-1.83)
POF 1.61 (1.22-2.12)
IUGR 1.66 (1.26-2.18)
Premature delivery 2.06 (1.58-2.18)
Preeclampsia 2.15 (1,76-2.61)
Abdominal obesity 2.26 (1.90-2.68)
Smoking 2.86 (2.36-3.48)
Hypertension 2.96 (2.57-3.39)
Diabetes 4.26 (3.51-5.18)
Early preeclampsia 7.71 (4.40-13.52)
Familiar Hypercholesterolemia 8.54 (5.29-13.80)
Yusuf 2004, Umans-Eckenausen 2002, Atsma 2006

Il “Mild cognitive
impairment” è più
frequente nelle
donne dopo una PE.
Le abilità più
frequentemente
interessate sono
quelle a carico di
funzioni esecutive,
verbali ed attenzione.

Take-home message
De Carolis, Aggiornamento medico, 2011

• Pregnancy History
• Medical and Family History
• Metabolic Syndrome Assessment

Counseling and Goal Setting
• Lifestyle Modifications:
• Blood Pressure Control
• Management of Lipid Disorders
• Insulin Resistance and Diabetes
• Aspirin Therapy

SINTESI DELLE
RACCOMANDAZIONI
Livello A:
ØLe donne con precedente storia di preeclampsia devono essere informate del
loro aumentato rischio di patologia cardiovascolare, devono essere inserite in
programmi di screening periodico con valutazione del rischio cardiovascolare e
devono essere edotte sulla modificazione dello stile di vita da adottare
(cessazione del fumo, riduzione di peso, aumento dell’attività fisica, dieta
adeguata).
ØAlle donne con persistenza dell’ipertensione arteriosa (Pressione arteriosa
140/90mmHg o 130/80mmHg in pazienti con comorbilità come insufficienza
renale cronica o diabete mellito) deve essere iniziata una terapia antipertensiva
Livello B:
ØValutare la terapia con statine in donne con pregressa preeclampsia e
dislipidemia
Livello C:
ØValutare la profilassi farmacologica con aspirina a basse dosi in base alla
stratificazione del rischio

Infiammazione/Endoteliopatia
/Aterosclerosi
• Similitudini tra PE e aterosclerosi
• Primum movens stato infiammatorio con
attivazione dei monociti/macrofagi
• Endoteliopatia da specie reattive dell’ossigeno
e particelle endotelio-tossiche
• Emissione endoteliale di chemochine,
citochine e molecole di adesione con
invasione leucocitaria del tessuto endoteliale
e ulteriore infiammazione

Fattori di Rischio per la PE2019

PE insulino-resistenza
• Early PE = insulino-resistenza
• Late PE ↑ insulino-resistenza

ty to
sess-
ontal
ML,
ably
tudy
ated
the
this
d to
pital
om-
ated
was
n of
oung
udies
brain
risk
to the pregnancy itself. Preeclampsia is considered to
be triggered by placental dysfunction, which results
in widespread endothelial dysregulation with consecu-
tive deficits in perfusion of several organs, including
the brain.22
Animal models of placental ischemia have
demonstrated impaired cerebral blood flow autoregu-
lation and increased blood–brain barrier permeabil-
ity.23
Interestingly, the cerebral insult may not be
limited to the time of pregnancy; a mouse model of
preeclampsia recently showed that after preeclamptic
but not normotensive pregnancy carotid injury leads to
enhanced vascular remodeling with increased vessel
fibrosis.2
This offers a plausible explanation for our
finding that the amount of cerebral damage increases
with time from pregnancy only in those women who
had preeclampsia. This could also be a major factor
underlying the increased risk of cerebrovascular disease
in women with a history of preeclampsia.1
Another possible link between altered brain architec-
0.81 ,0.01 0.20 20.73 0.60
0.11 ,0.01 0.03a
0.04 0.98
0.61 ,0.01 0.86 0.04 0.98
0.75 ,20.01 0.91 ,0.01 0.72
h-density lipoprotein; HOMA IR 5 homeostatic model assessment
Modelli animali di ischemia
placentare:
• ↑ della permeabilità della
barriera emato-encefalica e
inefficiente autoregolazione
del flusso ematico cerebrale
• Rimodellamento vascolare
carotideo con fibrosi

Preeclampsia in gravidanza e malattie renali
• 2,7 milioni di nascite in 1,4 milioni di donne
• 67.273 PE (4,9% dei casi)
• 410 hanno sviluppato malattia renale in gravidanza allo stadio
terminale

Risk of cardiovascular disease after pre-eclampsia
and the effect of lifestyle interventions: a
literature-based study
D Berks,a
M Hoedjes,b
H Raat,b
JJ Duvekot,a
EAP Steegers,a
JDF Habbemab
a
Division of Obstetrics and Prenatal Medicine, Department of Obstetrics and Gynaecology, b
Department of Public Health, Erasmus MC,
Rotterdam, the Netherlands
Correspondence: Dr D Berks, Erasmus MC, Department of Obstetrics and Gynaecology, Division of Obstetric and Prenatal Medicine, Doctor
Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands. Email d.berks@erasmusmc.nl
Accepted 2 November 2012. Published Online 26 March 2013.
Objective This study addresses the following questions. Do
cardiovascular risk factors fully explain the odds ratio of
cardiovascular risk after pre-eclampsia? What is the effect of
lifestyle interventions (exercise, diet, and smoking cessation) after
pre-eclampsia on the risk of cardiovascular disease?
Design Literature-based study.
Setting N/A.
Population or Sample N/A.
Methods Data for the calculations were taken from studies
identiﬁed by PubMed searches. First, the differences in
cardiovascular risk factors after pre-eclampsia compared with an
Results After correction for known cardiovascular risk factors, the
odds ratios of pre-eclampsia for ischaemic heart disease and for
stroke are 1.89 (IQR 1.76–1.98) and 1.55 (IQR 1.40–1.71),
respectively. After pre-eclampsia, lifestyle interventions on
exercise, dietary habits, and smoking cessation decrease
cardiovascular risk, with an odds ratio of 0.91 (IQR 0.87–0.96).
Conclusions Cardiovascular risk factors do not fully explain the
risk of cardiovascular disease after pre-eclampsia. The gap between
estimated and observed odds ratios may be explained by an
additive risk of cardiovascular disease by pre-eclampsia.
Furthermore, lifestyle interventions after pre-eclampsia seem to be
effective in decreasing cardiovascular risk. Future research is
DOI: 10.1111/1471-0528.12191
www.bjog.org
Maternal medicine
ns. Do
o of
effect of
ssation) after
from studies
in
ared with an
he effects of
imated.
ate these
Results After correction for known cardiovascular risk factors, the
odds ratios of pre-eclampsia for ischaemic heart disease and for
stroke are 1.89 (IQR 1.76–1.98) and 1.55 (IQR 1.40–1.71),
respectively. After pre-eclampsia, lifestyle interventions on
exercise, dietary habits, and smoking cessation decrease
cardiovascular risk, with an odds ratio of 0.91 (IQR 0.87–0.96).
Conclusions Cardiovascular risk factors do not fully explain the
risk of cardiovascular disease after pre-eclampsia. The gap between
estimated and observed odds ratios may be explained by an
additive risk of cardiovascular disease by pre-eclampsia.
Furthermore, lifestyle interventions after pre-eclampsia seem to be
effective in decreasing cardiovascular risk. Future research is
needed to overcome the numerous assumptions we had to make
in our calculations.
Keywords Cardiovascular disease, lifestyle interventions, pre-
eclampsia.
• I fattori di rischio CV non spiegano completamente
l’esito in malattia CV tardiva
• Il gap tra OR stimati e osservati spiegabile da un rischio
aggiuntivo della PE
• La PE stessa sarebbe un fattore di rischio piuttosto che
un marker di malattia CV
2013

C’é un paradosso….
• … la mortalità materna da malattia
cardiovascolare è più elevata nella
–early PE (insulino-sensibile) vs
–late PE (insulino-resistente)

J. Perinatol 2016
N=193 PE e parto ≥34 sett.
Verifica 6 settimane postpartum
Ipertensione persistente 21%

Preeclampsia and later
cardiovascular disease –
what do National
guidelines recommend?
Gitte Bro Schmidt, Martin
Christensen, Ulla Breth Knudsen
Pregnancy Hypertension 2017

Follow-up della Preeclampsia ed esiti a distanza - Sergio Ferrazzani

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