242 Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 4 (2014) 241–247
But we cannot, nor on present evidence, will we ever be able
to do so. Why is this?
There are several reasons, which I will attempt to sum-
marise: the heart of the problem is the complexity and var-
iability of the disorder, which is so daunting that every
specific statement about preeclampsia seems to have excep-
tions – it is truly a disease of exceptions.
The cause of pre-eclampsia appears to be the placenta –
in that the disorder can occur without a fetus as in hydatid-
iform mole, without a uterus as in abdominal pregnancy and
is resolved by delivery (of the placenta). On the other hand
some of the worst presentations are of women who are nor-
mal until delivery and then get a major crisis, eclampsia or
the HELLP syndrome, immediately afterwards, when the pla-
centa has gone.
The placental problem is poor uteroplacental circulation
secondary to inadequate remodelling of the spiral arteries
that occurs between weeks 8 and week 18 (poor placenta-
tion). The maternal symptoms and signs arise from maternal
endothelial dysfunction and an associated vascular inflam-
mation. But the placental pathology can occur without fea-
tures of pre-eclampsia and endothelial dysfunction can
arise in mothers without placental disease (maternal pre-
eclampsia).
This apparent confusion can be resolved in part by rec-
ognising that pre-eclampsia is not a disease but a syndrome
– encompassed by its defining features of new hypertension
and proteinuria that remit after delivery. A syndrome is sim-
ply an empirical definition of a clinical presentation that
demands action. It tells you nothing about pathogenesis.
One syndrome usually encompasses several conditions and
this is likely to be true of pre-eclampsia. The key here is to
acknowledge that there are many routes to pre-eclampsia;
that the final disorder arises from different mixes of environ-
mental and genetic factors, with different contributions from
the mother and the placenta. In terms of disease, the unique
feature of the latter is that two individuals are involved,
mother and baby, each with their different genetic make-ups.
This can explain the heterogeneity of pre-eclampsia: for
example the difference between early-onset disease with
its high preponderance of fetuses that are growth restricted
and prominent placental pathology in contrast to the late
onset disease, which may be associated with large for gesta-
tional age fetuses and routinely reveals little placental
pathology.
Finally, many very mild features of pre-eclampsia arise
towards term in normal healthy women. It is possible that
all women are destined to get the disorder. Timing is the
key feature, such that late gestation is a race against time:
will spontaneous delivery occur before pre-eclampsia or vice
versa?
doi:10.1016/j.preghy.2014.04.009
The role of maternal & fetal doppler in pre-eclampsia
Johanes C. Mose (Department of Obstetrics and
Gynecology, Padjadjaran University, Bandung, Indonesia)
Pre-eclampsia is associated with significant maternal
and fetal morbidity and mortality worldwide. Pregnancy
complicated by preeclampsia and/or by fetal growth restric-
tion are reported to have inadequate maternal vascular
responses to placentation. This defective vascular response
was due to the failure of second wave of endovascular tropho-
blast migration leading to both a reduced amount and depth
of trophoblast invasion of myometrium followed by the
development of placental hypoxia and ischemia that can be
measured biophysically by means of Doppler Ultrasound.
The role of Doppler in the screening and management of
preeclampsia would be reviewed in here focusing on uterine
artery, umbilicalartery (UA), middle cerebral artery (MCA)
and ductus venosus (DV) waveforms. The commonly used
flow velocity waveform (FVW) spectrum is used namely
resistance index (RI), systolic/diastolic ratio (S/D) or pulsatil-
ity index (Pl).
The presence or persistence of an early diastolic notch of
uterine artery over 24 weeks of pregnancy is predictive of
subsequent preeclampsia and or IUGR later on.
Umbilical artery Pl falls with gestational age, although
mean Pl is relatively stable after 30 weeks gestation. While
elevated indices are predictive of adverse outcome, absent
or reversed end-diastolic velocities (AREDV) are of particular
significance for growth restriction.
Mean MCA Pl increases to approximately 28 weeks gesta-
tion and then falls to term. Progressive hypoxemia results in
a reduction in MCA Pl and therefore values 5th centile are
regarded as abnormal. The ratio of UA/MCA Pl has been
widely used as an index of cerebral redistribution.
The 9 51 h centile for pulsatility index for vein (PIV) of
ductus venosus FVW falls from 0.9 at 20 weeks to 0.7 at
term, with values above this being regarded as abnormal.
The absence or reversal of atrial systolic forward flow of
DV FVW are of particular clinical significance.
By using Doppler in the early detection of preeclampsia
and its fetal complication namely growth restriction we
can arrange the management decisions and monitoring
strategy for preeclampsia.
doi:10.1016/j.preghy.2014.04.010
Pre-eclampsia – A disease of an individual couple
Gustaaf Albert Dekker
Preeclampsia still ranks as one of obstetrics major prob-
lems. Clinicians typically encounter preeclampsia as mater-
nal disease with variable degrees of fetal involvement.
More and more the unique immunogenetic maternal–pater-
nal relationship is appreciated, and as such also the specific
‘genetic conflict’ that is characteristic of haemochorial pla-
centation. From that perspective preeclampsia can also been
seen as a disease of an individual couple with primarily
maternal and fetal manifestations. Factors that are unique
to a specific couple would include the length and type of
sexual relationship, the maternal (decidual natural killer
cells) acceptation of the invading cytotrophoblast (paternal
HLA-C), and seminal levels of transforming growth factor-b
and probably other cytokines. The magnitude of the mater-
nal response would be determined by factors including a
maternal set of genes determining her characteristic inflam-
matory responsiveness, age, quality of her endothelium,
 Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 4 (2014) 241–247
obesity/insulin resistance and probably a whole series of
susceptibility genes amongst which the thrombophilias
received a lot of attention in recent years.
The maternal and fetal genomes perform different roles
during development. Inheritable paternal, rather than
maternal, imprinting of the genome is necessary for normal
trophoblast development. Preeclampsia may relate to a
‘hefty’ genetic conflict, or a mother unable to cope with a
‘physiologic’ genetic conflict.
The paternal contribution to preeclampsia, in addition to
the actual act of fertilization is demonstrated by:
1. The effect of the length of sexual relationship. After the
landmark retrospective study by Pierre Robillard in the
mid 1990s, the SCOPE consortium has recently
published the results of a large prospective study in
nulliparous women demonstrating the short sexual
relationships prior to conceiving are definitely indepen-
dent risk factors for both preeclampsia and ‘‘placental’’
small for gestational age.
2. The concept of primipaternity versus primigravidity in
2002. The primipaternity concept was recently chal-
lenged by Skjaerven et al. [35]. These investigators used
data from the Medical Birth Registry of Norway, a pop-
ulation-based registry that includes births that
occurred between 1967 and 1998. According to these
authors, prolonged birth interval and not paternity
change was the explanation for the increased pre-
eclampsia risk in multiparous women with a new part-
ner. More critical analysis of their data and various
subsequent studies have clearly demonstrated that
the primipaternity concept still stands.
3. Existence of the so-called ’dangerous’ father has been
demonstrated in various large population studies. Men
who fathered one preeclamptic pregnancy are nearly
twice as likely to father a preeclamptic pregnancy in a
differentwoman.
doi:10.1016/j.preghy.2014.04.011
The polymorphism analysis of A52G and C32T (KIR3DL2)
genes in patients with preeclampsia and normal preg-
nancy in Dr. Mohammad Hoesin General Hospital – South
Sumatera – Palembang.
Genetic and preeclampsia
Ferry Yusrizal
Preeclampsia is usually called as a disease of theories
where the real etipatology still unclear. Preeclampsia is a
medical complication of pregnancy which is characterized
by hypertension and proteinuria after 20 week pregnancy.
It is kown that preeclampsia has a clear genetic component.
Polymorphism of the KIR genes might be associated with the
genetic predisposition of preeclampsia. It is found that the
KIR3DL2 (Killer cell immunoglobuline-like receptor 3
domains, long cytoplasmic tail, 2 (KIR3DL2) gene expression
was obviously decreased in preeclampsia and assumed that
243
decreased KIR3DL2 gene expression weakened the protec-
tion of trophoblasts from being attacked by maternal immu-
nological cell and made in adequate trophoblast invasion in
early pregnancy. It causes insufficient utero-placental blood
flow and the defective piacentation.
doi:10.1016/j.preghy.2014.04.012
Molecular mechanisms and therapeutic implications of
the carbon monoxide/hmox1 and the hydrogen sulfide/
CSE pathways in the prevention of pre-eclampsia and
fetal growth restriction
Asif Ahmed (Vascular Medicine Unit, Aston University,
Birmingham B4 7ET, United Kingdom)
The exact aetiology of preeclampsia is unknown, but
there is a good association with an imbalance in angiogenic
growth factors and abnormal placentation (Ahmad and
Ahmed, 2004). The incidence of preeclampsia is reduced
by a third in smokers, but not in snuff users. Soluble Flt-1
(sFlt-1) and soluble endoglin (sEng) are increased prior to
the clinical onset of preeclampsia. Animals exposed to high
circulating levels of sFlt-1 and sEng elicit severe preeclamp-
sia-like symptoms. Smokers have reduced circulating sFlt-1
and cigarette smoke extract decreases sFlt-1 release from
placental villous explants.
An anti-inflammatory enzyme, heme oxygenase-1 (HO-
1) and its metabolite carbon monoxide (CO), inhibit sFlt-1
and sEng release. Women with preeclampsia exhale less
CO than women with normal pregnancies and HO expres-
sion decreases as the severity of preeclampsia increases. In
contrast, sFlt-1 levels increase with increasing severity.
More importantly, chorionic villous sampling from women
at eleven weeks gestation shows that HO-1 mRNA expres-
sion is decreased in women who go on to develop pre-
eclampsia. Collectively, these facts provide compelling
evidence to support the proposition that the pathogenesis
of preeclampsia is largely due to loss of HO activity. This
results in an increase in inflammation and excessive eleva-
tion of the two key anti-angiogenic factors responsible for
the clinical signs of preeclampsia. The identification of a pro-
tective role for HO-1 in pregnancy, offers HO/CO pathway as
a target for the treatment of preeclampsia. The cardiovascu-
lar drugs, statins, stimulate HO-1 expression and inhibit
sFlt-1 release in vivo and in vitro, suggesting statins have
the potential to ameliorate preeclampsia. The StAmP trial
is underway to address this and if positive, its outcome will
lead to the very first therapeutic intervention to prolong
affected pregnancies.
Hydrogen sulphide (H2S), a gaseous messenger produced
mainly by cystathionineY-lyase (CSE), is pro-angiogenic
vasodilator (Yang et al., 2008; Papapetropoulos et al.,
2009). We hypothesized that a reduction in CSE activity
may alter the angiogenic balance in pregnancy and induce
abnormal placentation and maternal hypertension. Plasma
levels of H2S were significantly decreased in preeclamptic
women (p < 0.01), which was associated with reduced
CSE message and protein expression in human placenta as
determined by real – time PCR and immunohistochemistry.
Inhibition of CSE activity by DL-propargylglycine (PAG) in