J.'.~"";i'

ACKNOWLEDGMENT
Above all and first of all, thanks to ALLAH, whose care
has supplied me with much strength to complete this work.
I wish to express my deepest thanks and profound gratitude to Prof.
Dr. Abd El-Moniem Abd El-Aziz Saleh. Professor ofObstetrics and
Gynaecology, Faculty of Medicine , Zagazig University, for giving me
the privilege of working under his supervision, for his continuos
encouragement and his eminent guidance, I am extremely grateful to him.
I am very grateful to Dr. Yousry Kamal Shallal ,
Assistant Professor ofObstetrics and Gynaecology, Faculty ofMedicine
Zagazig University , for his careful guidance, great help and kind
supervision all through this work, really, I am very appreciating his
support.
I am very grateful to Dr. Somia Hassan Abdalla. Assistant
Professor of Biochemistry, Faculty ofMedicine, Zagazig University for
her kindness and valuable assistance in the Biochemical studies ofthis
work.
I am very grateful to Dr. Hamed Mohamed Shalaby, lecturer of
Obstetrics and Gynaecology, Faculty of Medicine, Zagazig University
for his faithful guidance, keen supervision and kindness.
My deep thanks to the head of the Department and all the staff
members in Obstetrics and Gynaecological Department, Zagazig
University who had helped me directly or indirectly to do this work. and
lastly I extend my thanks to all the patients who had participated in
this study.

...,
Contents
• Introduction and aim of the work
• Review of literature
- Hypertensive disorder in pregnancy
- Etiology ofpreeclampsia
- Pathogenesis ofpreeclampsia
- Pathophysiology ofpreeclampsia
- Diagnosis and classification ofpreeclampsia
- Prediction ofPregnancy Induced Hypertension
- Complications and prognosis of preelcampsia
eclampsia
- Management ofpregnancy induced hypertension
- Lipoprotein (a)
• Patients and Methods
• Statistical Analysis
• Results
• Discussion
• Summary and conclusions
• Recommendations
• References
• Arabic summary
1-2
3
6
9
10
21
37
and 50
57
60
71
82
86
97
101
104
105
129

List of Abbreviations
: Apolipoprotein.
: Adult Respiratory Distress Syndrome.
: Antithrombin III .
: Colloid Osmotic Pressure.
: Central Venous Pressure.
: Disseminated intravascular coagulopathy
: Fibrin Degradation Products.
: Free Fatty Acids.
: Human Chorionic Gonadotrophin.
: High Density Lipoprotein.
: Syndrom manifested by Haemolytic anaemia,Elevated liver
Enzymes and Low platelet count.
: Low Density Lipoprotein.
: Lipoprotein (a).
: Pregnancy Associated Plasma Proteins A.
: Pregnancy Associated Plasma Proteins B.
: Positive End-Expiratory Pressure.
: Pre-eclamptic Toxaemia.
: Prostaglandin .
: Pregnancy induced hypertension.
: Plasma Protein S
: Transforming Growth Factor B.
: Thrombocytopenic Purpura
: Thromboxane.
: Vascular Cell Adhesion molecule.

List of Figures
) - Management ofmild preeclampsia 58
2 - Suggested management of severe preeclampsia carious 59
gestational stages
3 - Structure ofa typical lipoprotein partical 64
4 - Structure oflipoprotein (a) 64
5 - Representative standard curve. 76
6 - Histogram showing mean Lp(a) in control and study 93
groups.
7 - Histogram showing mean Lp(a) and mean systolic blood 93
pressure in control and study groups.
8 -Histogram showing mean Lp(a) and mean diastolic blood 94
pressure in control and study groups.
9 - Histogram showing mean Lp(a) and mean arterial blood 94
pressure in control and study groups.
10 - Histogram showing mean Lp(a) and mean ofSGPT in 95
control and study groups.
11 - Histogram showing mean Lp(a) and mean SGOT in 95
control and study group.
12 - Histogram showing mean Lp(a) and proteinuria in 96
control and study groups.

INTRODUCTION
AND
AIM OF THE WORK

Introduction
Introduction
Preeclampsia is a serious complication ofthe second halfof
pregnancy that occurs with a frequency of5% to 15% . This disease
is a leading cause of fetal growth retardation, infant and maternal
morbidity and mortality. In the placental bed, fibrin and platelet
deposition, thrombosis, and infarction occur and result in reduced
placental perfusion . In severe disease disseminated intravascular
coagulation may be present with platelet and fibrin deposition in
many organs, including the brain, liver , and kidneys . Altered
coagulability may be important in the pathogenesis ofpreeclampsia.
(Robets, 1993) .
Lipoprotein (a), a circulating lipoprotein particle, has been found to
enhance blood coagulation by competing with plasminogen for its
binding sites on fibrin clots and endothelial cells. This action is believed
to be mediated by a structural homology (> 90%) between
apoliopoprotcin (a) which is the carrier protein for lipoprotein (a) and
plasminogen. The activation of plasminogen to form plasmin is the
essential step necessary for the lysis of fibrin by plasmin
(Dahlen, 1994).
Many studies had demonstrated that elevated lipoprotein (a) levels
are associated with atherogenesis and myocardial infarction. (Wang, et
al. 1994) . Both in vitro and in vivo data indicate that lipoprotein (a)
levels are elevated in preeclampsia and associated with the severity ofthe
disease. This hypothesis is supported by observation of high lipoprotein
(a) levels in a single family with two cases of severe preeclampsia.
(Husby et al., 1996) .
I

Aim of The Work
Aim ofthe work
Is to determine alteration ofLipoprotein (a) level in Preeclampsia,
its predictive value and correltation with severity ofthe disease.
2

·.1"
_,;;t.
REVIEW
OF
LITERATURE

I . HYPERTENSIVE DISORDERS
IN PREGNANCY
Review ofLiterature
Elevated blood pressure during pregnancy is a challenging clinical
problem for which the approach to evaluation and treatment differs
substantially from that employed in nonpregnant patients.
First the diagnostic spectrum is broader since in addition to various
forms of chronic hypertension, the patient may have a short-lived
pregnancy specific form of hypertension i.e preeclampsia, The latter
disorder is accompanied by substantially greater maternal and fetal risks
than in uncomplicated essential hypertension. (Barron, 1995).
Pregnancy may induce hypertension in women who are
normotensive before pregnancy and may aggravate hypertension in those
that are hypertensive before pregnancy. The clinical and laboratory
characteristics of hypertension associated with pregnancy are difficult to
differentiate from those ofhypertension independent ofpregnancy.
As consequence, severe pregnancy-induced or pregnancy­
aggravated hypertension is frequently confused with other diseases
processes such as thrombotic thrombocytopenic purpura (TTP), acute
glornerulonephiritis, and chronic essential hypertension occuring during
pregnancy (Arias, 1993).
Preeclampsia is a disorder ofthe second half ofpregnancy, which
regresses after delivery. Its cause is not known but must lie within the
gravid uterus. Hence although preeclampsia is conventionally defined by
hypertension jt is not primarily a hypertensive disease. The raised blood
pressure and other maternal signs by which it recognized are secondary
features, reflections ofan intrauterine problem. (Redman, 1995).
3

Review ofLiterature
;. .: rhzr 211 il:Jba Jar; ce in
prostaglandin metabolism is central to pathophysiology ofpreeclampsia.
They cited an observed decrease in prostacyclin production and an
increase in thromboxan A2 prostacyclin ratio. While this hypothesis may
explain some hematological and biochemical peculiarities associated with
preeclampsia, it fails to show the primary etiology (Abramovicl and
Sibai, 1999).
A more basic abnormality ofpreeclampsia is usually generalized
arteriolar constriction and increased vascular sensitivity to pressor
peptides and amines, An early abnormality noted in women who develop
preeclampsia is failure ofthe second wave oftrophoplastic invasion into
the spiral arteries of the .uterus. As result, there is failure of the
cardiovascular adaptation to normal pregnancy, resulting in reduced
cardiac output and plasma volume. These abnormalities also result in
impaired tissue perfusion. (Abrarnovici and Sibai, 1999).
Incidence of hypertension disorders of pregnancy:
In some mysterious way, the presence of chorionic villi in certain
woman incites vasospasm and hypertension. Moreover, to effect a cure
the chorionic villi must be expelled or surgically removed. The
vasospastic hypertensive state and related pathological changes some how
induced by the presence of chorionic villi may not be so great that
pregnancy need to be terminated prematurely (Pritchard, 1978).
The hypertensive disorders of pregnancy acute and chronic,
regardless the cause, are among the most serious medical complications
that the pregnant female encounters. The majority of pregnancies
complicated by hypertensive diseases do reasonably well, however there
is a potential death to both the mother and the fetus (Zuspan, 1987).
4

-f
Etiology of Preeclampsia
Review ofLiterature
Endothelial cell activation or dysfunction appears to be the central
of theme in the pathogenesis of pre-eclampsia, but 'what causes these
endothelial changes in pre-eclampsia? Four hypotheses are currently the
subject ofextensive investigation. For the sake ofclarity these hypotheses
are described separately; however, it.should be stressed that they are not
mutually exclusive but probably interactive.
1- Placental ischemia.
According to the Oxford Group Of Researchers, pre-eclampsia is a
2-stage placental disease. The first stage is the process that affects the
spiral arteries and results in deficient blood supply to the placenta. The
second stage encompasses the effects ofthe ensuing placental ischemia
on both the fetus and the mother (Smarason et a1.,1993).
Placental ischemia as the cause ofendothelial cell dysfunction in
pre-eclampsia is an attractivecoucept, but several concerns are
conceivable that may dispute its validity. First, if placental ischemia is the
actual cause of endothelial cell dysfunction, one would expect a closer
correlation between the presence ofmaternal and fetal components ofthe
disease. However, this is not the usual finding in clinical practice. Next,
the chronology ofthe maternal components ofthe syndrome appears not
to fit with the placental ischemia hypothesis. The finding ofsome recent
studies suggest that endothelial cell involvement is already present in the
first trimester (Taylor et at, 1990)
2- Very low-density lipoproteins (VLDL) versus toxicity-preventing
activity.
In pre-eclampsia, circulating free fatty acids (FFA) are already
increased 15 to 20 weeks before the onset ofclinical disease. (Lorentzen
et al., 1994). Sera from pre-eclamptic women have both a higer ratio of
FFA to albumin cell uptake of FFA, which are further esterified into
6

Review ofLiterature
endothelial cell dysfunction characteristic ofpre-eclampsia (Easterling et
at, 1990).
Obesity is also associated with increased lipid availability,
increased delivery, of FFA to tissue, higher cholesterol and triglycerides
levels, insulin resistance, and hyperinsulinemia. (Unger, 1995).
Severe early onset pre-eclampsia is also associated with a high
incidence of underlying disorders such as protein S deficiency, activated
protein C resistance [factor V mutation], and anticardiolipin antibodies,
which may cause a more aggressive accelerated course ofthe disease by
including an abnormal interaction between endothelial cells, platelets,
leukocytes, and plasmatic coagulation and fibrinolytic factors.(Dekker et
aI., 1995).
8

Pathogenesis of pre- eclampsia
Review ofLiterature
The exact nature ofthe primary event causing pre-eclampsia is not
known. However, one of the initial events in this disease is abnormal
placentation, in which the main feature is inadequate trophoblastic
invasion ofthe maternal spiral arterioles. In normal pregnancy the wall of
the spiral arteries is invaded by trophoblastic cells and transformed into
large, tortuous channels that carry a large amount of blood to the
intervillous space and are resistant to the effects of vasmotor agents.
These physiologic changes are restricted in-patients with pre-eclampsia
(Brosens, 1977).
The anatomic and physiologic disruption ofnormal placentation is
thought to lead to altered endothelial cell function and multiple organ
damage (Shankil and Sibai ,1989). .
The majority of pregnant women with chronic hypertension have
essential hypertension. Rarely, the hypertension results from chronic
renal disease, renal artery stenosis, pheochromocytoma,
hyperaldosteronism, or other casuses (Lindheimer and Katz, 1985).
In pre-eclampsia, absence of normal stimulation of the renin­
angiotensin system, despite hypovolaemia, and increased vasucular
sensitivity to angiotensin II and norepinephrine can be explained by a
biologic dominance of TxA2 over prostacyclin. A reduction in urinary
excretion of prostacyclin metabolites precedes the development of
clinical disease, whereas TXA2 biosynthesis is increased in pre-eclampsia.
Increased TxA2 production in pre-eclampsia is largely derived from
platelets and the placenta. Placental prostacyclin production is reduced.
(Dekker and Sibai, 1998).
9

Pathophysiology of preeclampsia
Review ofLiterature
In order to understand the disease process and the prevalence ofthe
clinical signs of presentation it is important to understand the etiology
and pathophysiology of the condition, ifthis is done, early diagnosis and
potential prevention might be possible.
Unfortunately, the etiology of pregnancy induced hypertension is
still largely unknown. There has been much confusion over the role of
many pathological findings in this condition and it is important to
distinguish the signs caused by disease progression from those that are
markers of the underlying process. This can he done if there is a
recognizable stages for the disease process and it may be possible to use
these changes as predictors of patient at risk. Much has been written the
theories that have been put forward for the cause of preeclampsia
described the pathological features found in end-stage disease. It is not
necessary for hypertension in pregnancy to be manifested by
preeclampsia (Walker and Gant, 1997).
Moreover, signs found after maternal deaths from eclampsia may
have little prevalence to earlier stages of preeclampsia (Walker and
Gant, 1997). This may be the result of the disease process rather than the
cause. Because of this controversy about the etiology of preeclampsia it
was and still stated that preeclampsia is the disease of theories, any theory
should explain higher incidence in women who firstly be exposed to
chorionic villi (e.g. primigravida), in twin pregnancy, hydatidiform mole,
preexisting vascular disease, women who are genetically predisposed to
hypertension, and also should explain the improvement after expulsion or
death of the fetus. Dietary deficiency, vasoactive compounds and
endothelial dysfunction are implicated in the etiology of preeclampsia.
10,

-.--
Review ofLiterature
Changes involved in the pathophysiology of
(1) Vasospasm:
preeclampsia and eclampsia
Vasospasm is considered as the basic event in pathophysiology of
preeclampsia. This concept. first advanced by (Gilhard, 1981) and was
based on direct observation of small blood vessels in the nail beds.
occular fundi. and bulbar conjunctiva and it has been reported and
supported from histological changes seen in various' affected organs
(Walker and Gant, 1997). Vasospasm is alternating process with
segmental dilatation. which commonly accompanies the segmental.
arteriolar spasm. probably contribute further to the development of
vascular damage. since endothelial integrity may be compromised by
stretched dilated segments (Cunningham et al., 1993). Vascular
constriction causes resistance to blood flow and accounts for the
development of arterial hypertension. It is likely that vaso-spasm itself
also exerts a damaging effect on vessels. as the circulation in the vasa
vasorum is impaired leading to vascular damage. Moreover angiotensin II
causes endothelial cells to contract these changes lead to cellular damage
and inter-endothelial cell leaks through which blood constituents.
including platelets and fibrinogen are deposited subendothelialy (Walker
and Gant, 1997).
(2) Increased pressor response:
Normally pregnant women develop refractoriness to infused
vasopressors (catecholamines and angiotensin II). Increased vascular
reactivity to pressor hormones in women in early preeclampsia has been
identified by using either norepinephrin or angiotensin II and by using
vasopressin.• (Gant et aI., 1973) demonstrated that increased vascular
sensitivity to angiotensin II clearly preceded the onset ofpreeclampsia.
11

Review ofLiterature
(Oney and Kaulhausen,1982) found that nulliparous women who
remained refractory to the pressor effect ofinfused angiotensin II were
normotensive during pregnancy while women who subsequently became
hypertensive, lost this refractoriness weeks before the onset of
hypertension. Of women who required more than 8 ng/kg per minute of
angiotensin II to provoke a standardized pressor response between 28 and
32 weeks 90% remained normotensive throughout pregnancy. Conversely
, among normotensive nulliparous women who required less than 8 ng/kg
per minute at 28-32 weeks, to provoke pressor response, 90%
subsequently developed overt hypertension, also this was observed in
women with chronic hypertension who latter developed superimposed
pre-eclamspia (Walker and Gant, 1997).
(3) Supine pressor response:
A hypertensive response induced by having the women assumed
the supine position after lying laterally recumbant was demonstrated in
some pregnant women by (Gant et al., 1974) . The majority of
nulliparous women at 28-30 weeks, who had increased diastolic pressure
of at least 20 mmHg when the maneuver was performed, later developed
P.I.H. On the other hand, most women whose blood pressure did not
elevate remained normotensive. These women who demonstrated supine
response were also abnormally sensitive to infused angiotensin II, while
those without a hypertensive response were normally refractory. The
mechanism by which this maneuver incites a rise in blood pressure is not
clear but it is likely a manifestation ofincreased vascular responsiveness
or sympathetic overactivity in those who later will develop pregnancy
induced hypertension (Sander et at, 1995).
An identically performed study ofangiotensin II pressor response
were conducted in women whose pregnancies were complicated by
chronic hypertension and two groups were identified on the basis of
12
-.
..-

--f'
-,-
Review ofLiterature
clinical outcome on serial determination ofvascular reactivity ofinfused
angiotensin II. All women were refractory to angiotensin II between 21­
25 weeks, however , women who subsequently developed pregnancy
indueed hypertension began to lose this refractoriness after 27 weeks
(Gaut et aI., 1977).
It appears unlikely that the normally blunted pressor response to
angiotensin II is due to down regulation or decreased affinity of
angiotensin II vascular smooth muscle receptors. The metabolic rate of
angiotensin II, in women with P.I.H. is not altered many studies have
concluded that the blunted pressor response was due to decreased
vascular responsive mediated in part by vascular endothelial synthesis of
prostaglandins or prostaglandin like substances (Cunninghamm et al.,
1975). Refractoriness to angiotensin II in pregnant women is abolished by
large doses ofprostaglandin synthetase inhibitors (Evert et al., 1987).
(4) Imbalance between prostaglandins in P.I.H :
Previously the exact mechanism by which prostaglandins or related
substances mediated vasular reactivity during pregnancy was unknown
(Goodman et al., 1982).
It is now well established that prostacyclin (PGh) and thromboxan
A7, (TXA2) play an important role in the development ofpreeclampsia
(Friedman, 1988 and Walsh, 1990) . PGh which is synthesized
primarily by endothelial cells is a potent vasodialator and an inhibitor of
platelet aggregation. In contrast TxA2 which is synthesized mainly by
platelets is a potent vasoconstrictor and a stimulant of platelet
aggregation. PGh is elevated in normal pregnant women and decreased.
in pre-eclamptic patients. Because both are increased during normal
pregnancy it has been thought that a major mechanism in the
pathophysiologic changes of preeclampsia is an alteration in the ratio of
TXA2 and PGh with a change in the direction ofTxA2 dominance. The
importance of the change in this ratio in preeclampsia has been further
13

Review ofLiterature
proved by studies showing PGI2 biosynthesis preceding the development
ofclinical disease (Fitzgerled et al, 1987).
Schiff et al., (1988) reported a reduced incidence ofP.E.T. with
low dose aspirin treatment which can selectively suppress the synthesis of
platelet TxA2 without inhibiting the production of vascular PGI2.
So, evidence from maternal plasma, maternal urine, fetal plasma,
fetal vessels, amniotic fluid, and fetoplacental units has all supported the
concept that P.I.H. is associated with a functional imbalance between
PGI2 and TxA2(Schiff et al., 1988).
Gong et al., (1993) demonstrated, by using peripheral blood
mononuclear cells as a study model, increased TxA2 production in P.I.H.
patients both with and without proteinuria and this may playa role in the
development of hypertension and decreased placental blood flow. Of
primary importance in his study was that the sera from P.E.T. woman
with proteinuria contained a factor(s) that suppresses PGh production and
enhances TxA2 synthesis in peripheral blood mononuclear cells.
The cause of the imbalance between PGh and TXA2 seems to be
complicated and multifactorial. _To date there are several substances that
have been reported to be changed in P.I.H. and are also known to affect
the production of prostaglandins (PGs) in the humans (Gong et al.,
1993).
The first of these substances is progesterone which is capable of
inhibiting POI2 production and its level is found to be increased in P.I.H.
placentas (Walsh, 1988). The second is reactive oxygen species. It has
been reported that the activity ofreactive oxygen species is increased in
P.LH. and can change the pattern ofPGs production in favor of TxA2,
synthesis (Dekker et al., 1991 and Wisdom et al., 1991). The third is
mitogenic factor(s) which was recently discovered in the serum ofP.I.H.
patient by Taylor et al., (1990) and has the ability to stimulate fibroblasts
14
-f

Review ofLiterature
and is considered to be a growth factor' which in turn can generate
reactive oxygen species (Meier et al., 1989) and this can eventually lead
to imbalance of PGh and TXA2 as stated above . The fourth is
lipoxygenase products that have been suggested to suppress PGI2
synthesis and are known to be increased in P.l.H.
Both PGh and TxA2 are derived from arachidonic acid through the
action of cyclooxygenase. If the serum factor(s) described affect this
special enzyme the production of PGh and TxA2 should be equally
affected . However, the serum from P.E.T. women with proteinuria show
only 'significant increased TxA2 synthesis' and has little effect on PGh
formation. Therefore the reaction by this serum factor(s) may be located
on the levels of TXA2 and PGh synthetase rather on the level of
cyclooxygenase (Satoh et al., 1991).
At least two vasoconstrictor mechanisms may be operative III
preeclamptic women in whom arachidonic acid is converted by
cyclooygenase into thromboxane A2with an accompanying reduction of
prostacyclin and prostaglandin E2as evidenced by Cattela et al., (1990);
Mitchell and Koenig, (1991) and Tannirandom et al., (1991). This
pathway is responsive to low dose aspirin therapy. The second route is
via lipoxygenase pathway, which results in an increased placental
production of 15-hydroxy-eicosa-tetra-enoic acid. This inhibits
prostacyclin production, resulting in further vasoconstriction (Mitchell
and Koenig, 1991)
In conclusion, it has been shown that there is an imbalance
between PGh and TXA2 production in peripheral blood mononuclear cells
from patients with P.E.T., and a factor (s) was discovered especially in
those with proteinuria and found to contribute at least in part to the
abnornral production ofPGs however-the nature ofthis serum factor(s) is
not yet fully understood (Gong et al., 1993).
15

(5) Nitric oxide in P.tH. :
Review ofLiterature
The role of nitric oxide-endothelium derived relaxing factor or its
endothelial loss is unclear in P.I.H. , but experimental studies have
proved that withdrawal ofnitric oxide from pregnant rats and guinea pigs
resulted in the development ofa clinical picture similar to preeclampsia
(Weiner et al., 1989). Nitric oxide appears to be important in the
maintenance ofa low fetal vascular resistance in the placental circulation
(Myatt et al., 1991).
Fiona et al., (1996) found that. there were no significant
differences in maternal serum nitrites concentrations between P.I.H.
women and control group, but significant high serum nitrites
concentrations were found in the umbilical venous serum in fetuses of
P.I.H. group compared to control group. This increased nitrites
concentration in fetoplacental circulation in P.I.H. group may support the
hypothesis that, it may be compensatory response to improve blood flow
or may playa role in limiting platelets adhesion and aggregation.
Decreased nitric oxide release or production has not been shown to
develop prior to the onset ofhypertension .. Thus, changes in nitric oxide
release and concentrations in women with pregnancy induced
hypertension appear to be the consequence ofhypertension and not the
inciting event (Morns et al., 1996).
(6) Hyperplacentosis :
It was found that hyperplacentosis is a major factor influencing the
development of pre eclampsia and this may occur in diabetes mellitus,
multiple pregnancy, molar pregnancy and erythroblastosis fetalis
(Walker and Gant, 1997).
16
.. .'T

Review ofLiterature
next pregnancy or inability to recognize paternal antigens displayed by
the fetus (Walker and Gant, 1997).
Sutherland et al., (1981) postulated that the first pregnancy would
help to immunize the patient against any future pregnancy to the same
partner.
Redman et at, (1978) found a higher incidence of HLA
homozygosity in couples where mothers suffered from preeclampsia.
Chen et al., (1994) found abnormalities of lymphocytes function in
women with pregnancy induced hypertension. Other studies have
demonstrated activation of neutrophils within the maternal circulation
immunocytochemical studies have analyzed neutrophil elastase in term
placenta, decidua & myometrium in women with pregnancy induced
hypertension (Butterworth et al., 1991) . The vascular cell adhesion
molecule (VCAM-I) is elevated in the sera of P.l.H. women and
neutrophil activity partly mediated by this adhesion molecule, which
encourage adhesion to the vascular endothelium (Lyall et al., 1994) .
This could be part of the mechanism of endothelial cell dysfunction.
These changes may act by a direct cellular effects or through release of
cytokines which affect cellular function as they have been shown to affect
the production of prostacyclin and thromboxane in human mononuclear
cells thus affecting the vascular response in preeclampsia (Chen et al.,
1993).
Zhou et al., (1993), demonstated that there was an abnormality in
the expression of the adhesion molecules in the extravillus trophoblast in
pre-eclamptic pregnancies, and there was a failure in the expression of
those associated with successful invasion into the myometrium. This
could explain the secondary invasion that is associated with classical
placental lesion of preeclampsia,
18
.,

Review ofLiterature
Pregnancy associated plasma proteins A and B (PAPP-A and
PAPP-B) and plasma protein S are found only in the serum of pregnant
women. PAPP-A was reported to acquire its highest level in P.I.H. (Toop
and Klopper 1981).
PAPP-A being an inhibitor of fibrinolysis and also ofcomplement
fixation, has been sugessted to play a role both in coagulation and in
immunological changes in P.E.T. (Bischnoff, 1986). PPS, also found to
be increased in pregnancy and further increased in P.E.T. and there is a
close resemblence between PPS and antithrombin III and the former may
be regarded as the placental equivelant ofthe latter. PPS could be well
involved in coagulation and immunological changes in P.E.T. (Davey,
1986).
(8) Hyperdynamic circulation:
Recent studies suggested that, the increased maternal cardiac
output rather than the increased peripheral vascular resistance is the more
common hemodynamic feature occuring with preeclampsia.
Esterling et al., (1990) demonstrated that cardiac output values
were significantly higher in preeclamptic patients than in normotensive
ones. This elevation in cardiac output is already appeamt at 11weeks and
remains in the puerperium despite resolution of Hypertension also they
found that systemic vascular resistance of pre-eclamptic patients was
always less than that of normotensive patients and remained lower in the
postpartum period.
The finding of hyperdynamic left ventricular function and
decreased peripheral vascular resistance in preeclampsia may have an
important role in selecting the best .approachto the treatment of severe
hypertension in these patients by B-adrenergic blockers, rather than
vasodilator drugs and open the possibility of screening patients at risk by
measuring cardiac output at early gestation (Arias, 1993).
19

Review ofLiterature
On the other hand, the increase in the intra-vascular volume that
normally occurs during pregnancy is minimal or completely absent in
patients with preeclampsia. This limited blood volume expansion is
probably the result of generalized vasoconstriction of capacitance vessels
(Pickles et aI., 1989).
20

.....
,-
Review ofLiterature
Diagnosis And Classification Of Preeclampsia
According to the American College of Obstericians and
Gynecologists (ACOG)1985 , the diagnoses ofhypertension in pregnancy
is made by anyone ofthe following criteria.
1- A rise of30 mmHg or more in systolic blood pressure.
2- A rise of 15 mmHg or more in diastolic blood pressure.
3- A systolic blood pressure of 140 mmHg or more.
4- A diastolic blood pressure of90 mmHg or more.
These alternations in blood pressure should be observed on at least
two different occasions at least 6 hours apart. (Cunningham et al., 1997)
Hypertension in pregnancy is classified .Into the following
groups:
1- Pregnancy-induced hypertension.
a. Preeclampsia.
b. Eclampsia.
2- Chronic hypertension of whatever cause but independent of
pregnancy.
3- Preeclampsia or eclampsia superimposed on chronic hypertension.
4- Transient hypertension.
Each of these factors of hypertensive disorders defined by
American Colleague of Obstetricians and Gynecologists
(ACOG) as following:
Pre-eclampsia:
Hypertension associated with proteinuria, greater than 300 mgm/24
hours urine collection or greater than 100mgmJdl in at least 2 random
urine samples 6 hours or more apart, and/or greater than +1 pitting edema
after 12 hours rest in bed or weight gain of5 pounds or more in 1 week or
both after 20 weeks ofgestation (Chesley et at, 1985) (Arias; 1993). Or
a syndrome which becomes detectable in the second halfofpregnancy
21

Review ofLiterature
which is defined in terms ofthe new development Ollljp-:nl;lIsiun and
proteinuria. (De Swiet, 1995).
Proteinuria:
Protein is always present in urine in small amounts and it increases
in normal pregnancy. The presence ofmeasurable protein can be due to
an increase in the normal renal leakage or a specific increase from renal
damage. The amount of protein found in urine will depend on the amount
passing across the glomerulis and the amount reabsorbed by the tubules.
The classic lesion in pre-eclampsia is glomerular endotheliosis. This is
not a sign of damage but a pathophysiological change that will recover
within days of delivery. It is alway's associated with proteinuria which
consists mostly of albumin that implies leaks across the glomerular
memberance. It is important to note that in more severe disease,
proteinuria is less specific being associated with tubular proteins (James,
1998).
Edema:
The pathological edema of preeclampsia is easily confused with
physiological edema found in 80% of normal pregnant women
physiological edema has not been shown to be precursor ofpathological
edema (De Swiet, 1995).
In one of the prospective studies, pregnant women with no edema
or early and late onset edema, all had a similar incidence of preeclampsia
(Robertson, 1971).
During normal pregnancy there is a moderate fall in colloid
osmotic pressure of the plasma and rise in hydrostatic pressure in the
capillaries. This tends to increase fluid filteration from the intravascular
compartments, but this is compensated by fluid reabsorption . For all
these reasons, the detection ofedema is not useful clinically, nor should
edema be included in the definition' of preeclampsia. Development of
22
',,"

Review ofLiterature
edema is associated with higher rate ofweight gain, hence the numerous
reports associating excessive weight gain with the development of
preeclampsia (De Swist , 1995).
Eclampsia:
Convulsions occurring in a patient with preeclampsia without
evident neurological disorder (Cunningham et al., 1997).
Chronic hypertenion :
The presence of sustained hypertension more than 140/90 mmHg
or higher before pregnancy or before 20· weeks.(Cunningham et al.,
1997).
Preclampsia or eclampsia superimposed on chronic hypertension:
The occurrence of preeclampsia or eclampsia in women with
chronic hypertension, to make this diagnosis it is necessary to document a
rise of 30 mmHg or more in systolic or 15 mmHg more in diasolic blood
pressure, associated with proteinuria, edema or both, and diagnosis
requires documents ofunderlying chronic hypertension (Cunningham ct
al., 1997).
Transient hypertension:
The development of hypertension during pregnancy or early
puerperium in a previously normotensive women whose pressure
normalizes within 10 days postpartum.
23

1. Gestational hypertension (without proteinuria).
a- Developing antenatally.
b- Developingfor the first time in labor.
c- Developing for the first time in the purperium.
2. Gestational proteinuria (without Hypertension).
a- Developingantenatally.
b- Developingfor the first time in labor.
c- Developingfor the first time in the purperium.
3. Gestational proteinurichypertension (Pre-eclampsia).
a- Developingantenatally.
b- Developing for the first time in labor.
c- Developing for the first time in the purperium.
II. Chronic hypertension and chronic renal disease:
Review ofLiterature
Hypertension and/or proteinuria in pregnancy in a woman with
chroinc hypertension or chronic renal disease diagnosedbefore, during,
or after pregnancy. This group is subdividedinto.
1. Chronichypertension(withoutproteinuria).
2- Chronic renal disease (proteinuria with or without hypertension).
3- Chronic hypertension with superimposed pre-eclampsia, proteinuria
Developing for the first time during pregnancy in a woman with Known
chronic hypertension.
III. Unclassified hypertension and/or proteinuria:
Hypertensionand/or proteinuriafound either:
1. At first examinationafter the twentieth week of pregnancy(140 days)
in a woman with known chronichypertension or chronic renal disease, or
2. During pregnancy, labor, or the purperium, in a case in which
informationis insufficient to permit classification?
25
...-

This category is subdivided into:
a- Unclassified hypertension (without proteinuria).
b- Unclassified proteinuria (without hypertension).
Review ofLiterature
c-Unclassified proteinuric hypertension. (Davey and Mac Gillivary,
1988)
DIAGNOSIS OF SEVERE PREECLAMPSIA
Symptoms
For the diagnosis of preeclampsia, the committee on terminology
requires acute hypertension in the latter half of pregnancy with
proteinuria, or facial, digital or generalized edema or both (Chesley,
1985).
HEADACHE:
Headache is unusual in milde cases but is increasingly frequent in
more. severe disease. It is often frontal but may be occipital, and it is
resistant to relief by ordinary analgesics. In women who develop
eclampsia, severe headache almost invariably precedes the first
convulsion (Cunningham et al., 1997). The cause ofheadache is usually
inadequate blood pressure control, and it is an indication for aggressive
treatment with hypotensive agents (Arias, 1993).
EDEMA:
Edema is included in the classic definition of preeclampsia and is
used as a diagnostic feature in several classification system of
hypertension in pregnancy. Pathological edema perhaps most notable in
the face, occurs in 85 per cent of women with preeclampsia and is
associated with a rapid increase in weight (Thomson et al., 1987).
26

Review ofLiterature
However, severe preeclampsia anu eclampsia 1".1h occur v' HHUUl
edema and the perinatal mortality rate has been shown to be higher in
preeclampsia without edema than in preeclampsia with edema
(Vosburgh, 1976).
Significant edema can also be, found in 80 per cent ofnormal
pregnancies. In a prospective study ofedema in pregnancy the incidence
of hypertension did not differ between those with and without edema
(Robertson, 1971).
EPIGASTRIC PAIN:
Epigastric or right upper quadrant pain often is a symptom of
severe preeclamsia and may be indicative of imminent convulsions. It
may be the result ofstretching ofthe hepatic capsule, possibly by edema
and hemorrhage, (Cunningham et al., 1989).
Visual Disturbance:
Bosco (1961) reported that headache, scotoma and blurred or
decreased vision are common presenting symptoms demanding careful
consideration.
OLIGURIA:
Oliguria is defined as urine output

Review ofLiterature
though the blood pressure remains within the normal range, and the
woman has appoximately a 60% chance of developing preeclampsia. If
the test is negative, the likelihood of patient developing preeclampsia is
about 1 in 100 (Dekker and Sibai, 1991).
Isometric exercise test: Isometric hand - grip exercise is known to
increase systemic arterial blood pressure, presumably resulting from
increased systemic vascular resistance. Degani et al., (1985) subjected
one hundered healthy primigravid women to an isometric hand - grip
exercise test between 28 and 32 week's gestation. Each woman was
placed in the left lateral position, and blood pressure was recorded at
regular intervals until it remained stable. The patient then was instructed
to press an inflated cuff of a calibrated sphygmomanometer to maximal
voluntary contraction for 30 seconds for a three minute period of
sustained isometric handgrip exercise. The patient then compressed the
inflated sphygmomanometer at a tension level of 50% ofthe subject's
previously determined maximal voluntary contraction. Blood pressure
measurements were taken on the passive ann, and an increase in the
diastolic pressure of 20 mmHg was taken as a positive isometric pressor
response.
The level of mean arterial blood pressure during the second
trimester is a poor predictor of the future development ofeclampsia and
might give the clinician a false sense of security when it is negative « 90
mmHg) (Chesley and Sibai, 1987).
Blood pressure alone is not always a dependable indicator of
severity. For example, an adolescent woman may have 3 + proteinuria
and convulsions while her blood pressure is 140/85 mmHg, whereas most
women with blood pressure as high as 180/120 mmHg do not have
seizures. (Cunningham et al., 1989).
29

Review ofLiterature
It is an indicator of disease severity and its presence is associated
with substantial increase in the perinatal mortality rate (Naeye and
Friedman, 1979).
Davery and MacGilIiveray (1987) have suggested that proteinuria
should be classified as severe if there are 2:: 3gm protein in a 24hr
collection.
The clinically oriented classification of the American Committee
on Classification does not require proteinuria for the diagnosis of
preeclampsia because it is usually of late onset in the course of the
disease that the onest of convulsions may precede its appearance
(Chesley and Sabiai, 1988).
Retinal changes and ocular manifestations:
Retinal vasoconstriction is the most obvious fourth sign in manifest
preeclampsia, along with the classic symptom triad of hypertension,
edema and proteinuria. The tonic constriction of retinal arteries may
appear like a corkscrew. (Hollwich, 1979).
Beside the narrowing of the vessels there is a slight edema of the
posterior pole of the retina and the disc shows a slight lack ofdefinition
of its margins. Cotton • wool exudate, retinal stria, and yellow - white
focal retinal lesions may develop (Fastenderg et al., 1980)
If the pregnancy is not terminated, the retinal edema may progress
to flat detachment of the retina. The incidence of serious retinal
detachment is about 1.2 per cent in preeclampsia and about IDA per cent
in eclampsia (Fry, 1929).
Bosco (1961) reported that retinal detachment is usally bilateral
and frequently affects the lower portion of the retina and that it resolves
spontaneously in the majority of cases within 2 weeks of labor.
31

Review ofLiterature
Blindness is an uncommon symptom of eclampsia with a 1 to 3
percent incidence (Dieckman, 1952). There are different types of
blindness associated with preeclampsia.
... Retinal blindness may be secondary to serous detachment ofthe
retine (Gass and Pautler, 1985). or retinal vascular thrombosis
(Carpenter et at, 1953).
... Acute ischemic optic neuropathy as a result of impairment ofthe
blood supply to the prelaminer portion ofthe optic nerve head (Beck et
at, 1980). This hypothesis is based on ophthalmoscopic findings and is
currently not well founded.
* Cortical blindness may be present in an eclamptic patient alone
(Lau and Chan, 1987). or with impaired conscious level (Beeson and
Duda, 1982; Colosimo et aI., 1985).
Renal changes:
In a study ofpatients with severe preeclampsia and severe oliguria
unresponsive to a single fluid challenge, Clark et al., (1986), described
three hemodynamic subsets:
- Most patients were found to have low wedge pressures, mild to
moderate elevations of systemic vascular resistance, and normal cardiac
output. In these patients oliguria was associated with inadequate preload
and responded rapidly to further crystalloid infusion.
- A second group of patients were oliguric on the basis ofsevere
systemic vasospasm and inadequate cardiac output. Oliguria in these
patients responded to aggressive after load reduction.
- A final group ofpatients appeared to be hypertensive principally
on the basis of elevated cardiac output. These patients exhibited high
cardiac output, hyperdynamic ventricular function, normal or mildly
increased systemic vascular resistance and adequat preload, yet they were
oliguric with urinary specific gravities exceeding 1030. Analysis ofthe
32
-_ .....

Review ofLiterature
above hemodynamic parameters implies the presence of selective renal
arteriospasm out of proportion to systemic vasospasm (Clark and
Cotton, 1988).
Hankines et al., (1984) documented the relationship between
elevated pulmonary capillary wedge pressures and delayed spontaneous
postpartum diuresis in eclamptic women. They hypothesized that this
phenomenon was secondary to the mobilization of extravascular fluid
before diureses. Such observation may account for the occurance of
postpartum cerebral and pulmonary edema in patients with pregnancy
induced hypertension. Under these circumstances oliguria could
potentially play an important role in the pathogenesis of these
preeclampsia - related complications.
The blood and urine laboratory values are used to calculate urine to
plasma ratios of sodium (DIP Na), creatinine (UIP Cr), urea nitrogen and
osmolality Free excretion of sodium is calculated by the formula (U/P Na
+ UIP Cr) x 100. The renal failure index was also calculated by dividing
urinary sodium concentration (mEqlL) by (UIP Cr). The interpretation of
urinary diagnostic indices was based on the criteria proposed by Miller et
al (1978).
Table (2)
Urine osmolality (mosm/kg ofwater)
Urine sodium (mEq/L)
Urine / plasma urea nitrogen
Urine I plasma creatinine
Renal failure index
Fractional excretion sodium
Urinary diagnostic indices in oliguria
(Miller et al., 1978)
33
>500 8 40

Review ofLiterature
these women had underlying hypertensive cardiovascular factors
(Cunningham et at, 1986).
The patients usually have generalized arterial vasospasm resulting
in increased systemic vascular resistance (increased after load), reduced
plasma volume (decreased preload), and increased left ventricular stroke
work index (hyperdynamic heart). In addition, renal function is impaired,
serum albumin is reduced, and capillary premeability is increased due to
endothelial cell injury. Consequently, the above changes will predispose
these patients to an increased risk of pulmonary edema (Benedtti et at,
1985).
There are clinical differences between pulmonary edema of organic
heart disease and that of preeclampsia. Most cases of patients with
preeclampsia occur in young women without previous histories of heart
disease, with normal electrocardiogram, and without cardiomegally on
chest x-ray films or echocardiogram. Also, the course ofthe disease in the
preeclamptic patient is characterized by its slow response to therapy.
Swan - Ganz catheter insertion is the best to diagnose the altered
hemodynamics of pulmonary edema. Ifit is not feasible to insert a Swan ­
Ganz catheter, a CVP line should be used. However CVP measurements
are not as reliable as the pulmonary capillary wedge pressure (PCWP)
(Benedetti et at, 1985).
THE CENTRAL NERVOUS SYSTEM:
The brain can be involved in the pathological process of
preeclampsia with eclampsia being one of the most extreme clinical
manifestations of this involvement. The pathological features that can
occur include cerebral edema, cerebral hemorrhage, petechial
hemorrhages, thrombotic lesions and fibriboid necrosis (Hibbard, 1973;
Sheehan and Lynch, 1973; Lopez. Liera et al., 1976). The major
causes of maternal mortality from severe preelampsia are cerebral
hemorrhage and cerebral edema (Benedtti and Quilligan, 1980).
These changes are thought to be attributable to vascular damage.
Cerebral edema is not a constant feature but may be seen on
computerized tomography (CT) scanning of the brain in eclamptic T
35

Review ofLiterature
patients (Naheedy et al., 1985; Richards et al., 1988). The latter study
showed cerebral edema to be present on CT scanning in 27 of43 women
with neurological complications secondary to preeclampsia - eclampsia
and this correlated with the duration ofintermittent seizures.
Computerized tomograhy (CT) scanning shows that petechial
cortical hemorrhages are most common, and these often involve the
occipital lobe; however, the parietal and frontal lobes are also involved.
(CT) scanning rarely describe diffuse cerebral edema or overt
hemorrhage into the white matter, basal ganglia, or pons (Brown et al.,
1988).
36

111- Biochemica markers:
* Uric acid.
* Urinary calcium kallikrein and creatinine excretion.
* Urinary excretion ofprostacyc1in metabolites.
* Platelet angioetensin II receptors.
* Platelet calcium response to arginine vasopressin.
* Enzymes and Hormones,
- Low unconjugated estriol concentration.
- Maternal Serum inhibin A
- Human choronic gonadotrophin (HeG).
- Serotonin
- Atrial Natriuretic peptide.
* Clearance ofdehydro-iso-androsterone sulfate.
IV· Hematological markers:
* Plasma velum , hematocrit and hemoglobin.
* Platelets count platelet volume.
*Plasma factor VIII - related antigen activity.
* Ratio offactor VIII to coagulant factor VIII.
* Antithrombin III levels.
*Thrombin antithrombin III levels.
* Fibronectin.
V - Ultrasonographic evaluation:
* Doppler wave forms of utero-placental circulation.
1 - Standard methods ofantenatal care:
Review ofLiterature
Antenatal visits are arranged monthly between 20-28 weeks,
biweekly up to 36 weeks. and weekly there after until delivery. These
visits are dominated by a check of blood pressure, urine and by
determination of weight gain. The development ofpreeclampsia may be
predicted on the basis of these standard variable has been addressed in
several retrospective and some prospective studies. (Dekker and Sibai
1991) .
38

Proteinuria and microalbuminuria :
Review ofLiterature
The most recent classification ofpreeclampsia require proteinuria
(defined by excretion of 300mg or greater in 24hour urine specimens; this
usually correlates with 30mg/dL on random sampling (O'Brien, 1992) .
Micro-albuminuria 24 urinary albumin excretion> 30mg/L
(30uglm) might become a clinical tool for predicting pre-eclampsia.
Das et at, (1996), Lopez-Espinoza et al., (1986) found that
proteinuric pre-eclampsia was not preceded by a phase of increasing
albumin loss which could be detected by sensitive radio-immune assay
techniques.
Weight Gain:
A sudden increase in weight may precede the development of
preeclampsia, and indeed , excessive weight gain in some women is the
first sign. A weight increase of about 1 pound per week is normal, but
when weight gain exceeds more than 2 pounds in any given week, or 6
pounds in a month, developing preeclampsia should be suspected, the
suddenness of excessive weight gain is characteristic ofpreeclampsia
rather than an increase distributed throughout gestation. Such a weight
gain due almost entirely to abnormal fluid retention and is usually
demonstrable before visible signs of non-dependent edema, such as
swollen eyelids and puffy fingers. In cases of fulminating preeclampsia.
Or eclampsia, fluid retention may be extreme and in these women, a
weight gain of 10 or more is not unusual. The total weight gained during
pregnancy, however, probably has no relation to preeclampsia unless a
large component ofthe gain is edema. Stringent restriction ofweight gain
is more likely to be detrimental rather than beneficial to both mother and
fetus (Cunningham et al., 1994).
40
-...
:....:...
"'

Review ofLiterature
gestation while there was no difference reported in urinary excretion rates
ofcalcium between normotensive and hypertensive pregnant women.
Millar et al., (1996), suggested that measurement of inactive
urinary kallikrein, creatinine in a random urine sample collected between
16-20 weeks gestation could be used for early prediction of pre­
eclampsia.
Urinary kallikrein excretion has been shown to increase in
normotensive pregnancy , whereas in preeclampsia reduced levels as
compared to non-pregnant subjects have been found (Baker, 1993).
3- Urinary Excretion of Prostacyclin Metabolites:
Evidence is accumulating that a relative deficiency of vascular
prostacyclin plays an important role in the development ofpreeclampsia.
(Fitzgerald et al., 1987) reported that a reduction in the urinary excretion
of 2,3-dinor-6 keto- prostaglandin FI, a major metabolite ofprostacyclin,
precede the development of clinical diseas.
4 - Platelet angiotensin II receptors:
(Dekker and Sibai 1991), showed that a physiologic fall in platelet
angiotensin II binding occur in early pregnancy, which is parallel to that
ofthe vascular response to angitensin II.
lt was found that platelet angiotensin II receptors are increased in
pre-elcampsia, problably as an expression of the altered angiotensin II
levels; this increase was shown to precede the increase in blood pressure.
S - Platelet calcium response to arginine vasopressin:
An increase in the sensitivity of platelet calcium to argmme
vasopressin was proposed to be useful as an early predictor of subsequent
pre-eclampsia, it was shown that the sensitivity ofplatelet intracellular
calcium levels to arginine vasopressin in pateint with subsequent pre­
eclampsia is already increased at the end of first trimester, as compared
with normotensive pregnancy (Zemel et al, 1990) .
43

Review ofLiterature
peptides include an increase in salt and water excretion, inhibition of
angiotensin or norepinephrine-mediated vasoconstriction and reduction in
secretion ofrenin and aldosterone (O'brien, 1990).
The concentrations of atrial natriuretic peptides are increased in
patients with various forms ofpregnancy-induced hypertension However,
the etiology of this increase in hypertensive disorders ofpregnancy is
unknown (Thomson et at, 1987; Miyamoto et at, 1988).
Several factors mitigate against a role for atrial natriuretic peptide
measurement in prediction ofpreeclampsia :
- The rise in these values appear to occur after the onset ofhypertension
and seems to mirror the rise in blood pressure (Hirai et al., 1988).
2 - An elevation may be seen in patient with essential hypertension
(SagneIJa et at, 1986).
3- The measurement requires inhibition of digestion at time ofsampling
and extraction before immunoassay. The complexity of the assay
accounts for a large part of variability in results (Miyamoto et al.,
1988).
O'brien (1990) reported that, it appears that, measurement ofatrial
natriuretic peptides will not provide a clinically important diagnostic aid
in the detection ofpreeclampsia.
IV- Hematologic markers:
1 - Plasma volume, hematocrit and hemoglobin :
The average plasma is fewer in-patients with pre-eclampsia. There
IS evidence that plasma contraction may precede the blood pressure rise
in pre-eclampsia at least in some of cases. The contraction ofplasma
volume that is often observed in pre-eclampsia may be revealed by an
elevation of or rise in hemoglobin concentration or hematocrit. (Hays et
al., 1985).
46

Review ofLiterature
appear that measurement ofserum iron concentration, although valuable
in confirmation, would be a poorpredictor ofpreeclampsia.
4 - Coagulation factors:
Evidence for the occurrence of abnormal coagulation processes and
platelet activation was originally based on the finding as early as 1893, of
fibrin deposits and thrombi in vessels ofvarious organs ofwomen who
died of eclampsia. In later years, all factors of extrinsic and intrinsic
coagulation system have been extensively studied in women with
preeclampsia. A complicated coagulation index has been proposed to
predict the clinical prognosis of pre-eclampsia (Davis, and Prentice,
1992).
Parameters which have been reported to indicate the subsequent
development of the disease are anti-thrombin III and factor VIII
consumption increase levels of Beta-thrombglobulin, a platelet specific
released during platelet activation have also been reported in women with
pre-eclampsia (Redman et at, 1977) .
Weiner and Brandt, (1982) reported lower levels ofantithrombin
activity in women with preeclampsia as compared to healthy pregnant
women. The level ofantithrombin III (AT III) activity began to decline
as much as 13 weeks prior to the development ofclinical manifestation.
Recently, attention has been focused on plasma level of fibronectin,
which is glycoprotein involved in coagulation, platelet function, tissue
repair, and the vascular endothelial basement membrane. Fibronectin
level was found to be markedly elevated in pre-eclamptic patients and
correlated with low antithrombin III levels and with the degree of
proteinuria (Saleh et at, 1987).
5· Fibronectins :
Fibronectins are a group of glycoproteins dispersed throughout the
body that serve two major functions.
48
"l-

....
-,:-"
Review ofLiterature
a. Tissue fibronectins (insoluble fibronectin) present at the basement
membranes of most tissues, appear to play an important role in tissue
adhesiveness and cell-to-cell interaction.
b. Plasma fibronectin (soluble fibronectin) functions as a non-specific
opsonin important in the early phagocytic response to bacteria
(Mosesson et al., 1980).
Because fibronectin is present in the vascular endothelial basement
membrane, moreover, circulating fibronectin levels may serve as a
. marker for endothelial damage or disruption (Stubbs et at, 1984).
The plasma fibronectin concentration rises approximately 20% during
the third trimester of normal pregnancy and remains elevated throughout
the six postpartum week (Hess et al., 1986).
Lockwood et al. (1990) reported that many studies demonstrated
increased plasma levels ofendothelial originated fibronectin precede the
clinical signs of preeclampsia and may be useful for prediction ofthe
disease.
O'Brien (1990) reported that there is a clear association between
preeclampsia and elevated levels ofplasma fibronectin, several methods
of assay have been reported, the most common is turbidimetric method.
This method is easy, inexpensive and suitable for automation, and thus
could be performed easily in most clinical settings.
Saleh et al. (1988) reported that fibronectin is a better marker for
preeclampsia than either antithrobmin III or a2-antiplasmin and is a
better correlate of reduced plasma colloid oncotic pressure than is
proteinuria.
The diagnosis value of fibronectin determination as a predictor of
preeclampsia was studied by Lazarchick et al., (1986). In that study,
plasma was studied for fibronectin ofpregnancy women. Using a cut off
point value of 400 ug/ml. 94% ofsubjects who developed preeclampsia
49

Review ofLiterature
demonstrated an elevation before the onset ofhypertension and in 76%
occurred at least 1 month before the onset of hypertension. So it appears
that fibronectin as an excellent laboratory marker for preeclampsia.
Magann and Martin (1995) reported that plasma fibronectin
concentration is markedly elevated in patients with pre-eclampsia. Plasma
fibronectin increased 3.6 ±1.9 weeks earlier than the onset of
hypertension and/or proteinuria.
Complications And Prognosis Of Preeclampisa And Eclampsia
Maternal complications:
Fetal complications :
I. Maternal morbidity:
A. Immediate complications:
I. Maternal morbidity.
II. Maternal mortality.
1. Fetal morbidity.
II. Fetal mortality.
There are many complications that are although uncommon in PIH
yet potentially lethal, especially ifseveral complications arise in the same
individual. These complications are stated in Wein (1979).
1. Cerebrovascular complications:
Cerebral edema:
Symptomatic cerebral edema developed in almost 6% ofwomen
with eclampsia. Its genesis probably represents a continuum ofcentral
nervous system lesions that result from eclampsia. We postulate that
women with symptoms of extensive cerebral edema have a cytotoxic
edema caused by ischemia that is intensified by a vasogenic edema
associated with sudden ofsevere hypertension. (Cunningham & Diane
.,2000)
50
­ .,

....
'I, -
2. Occular complications:
Review ofLiterature
According to Richards (1986) , only IM3% ofcases ofPIH and
eclampsia suffer from temporary blindness due to one ofthe following
causes:
MCentral retinal arteriolar or venous thrombosis.
MEdema ofthe retina.
MCentral disturbance of the visual center in the occipital lobe by edema or
hemorrhage.
MDetachment ofthe retina.
- Disturbance ofthe optic nerve.
- Psychogenic disturbances.
- Intracranial venous thrombosis.
3. Rena/complications:
Acute renal failure is an extremely rare complication of P.I.H
eclampsia and its development is usually a result ofeither acute tubular
necrosis or rarely bilateral cortical necrosis.
The pathogenesis ofacute renal failure continues to be the subject
of extensive investigations and several pathologic mechanisms have been
implicated as possible etiologic factors. The occurrence ofacute renal
failure is usually associated with P.I.H complicated by abruptio placental
and disseminated intravascular coagulopathy (DIC) (Sibai et aI., 1990) .
Therapeutic principles in the management of acute renal failure
include supportive and dialytic treatment until renal function recovers.
Once the maternal condition is stabilized, if the fetus is mature, delivery
should be effected. Successful peritoneal dialysis and hemodialysis have
been reported for the treatment of acute renal failure in pregnancy.
Peritoneal dialysis is associated with a lower risk of hypotension and
rapid fluid shifts. (Hov, 1987).
51

4. Hepatic complications:
Review ofLiterature
Ruptured subcapsular hematoma ofthe liver, liver rupture is a life­
threatening but fortunately, relatively rare complication (Sibai et al.,
1982) . In most instances, rupture involves the right lobe and is preceded
by the development ofa parenchymal hematoma. The condition usually
presents with severe epigastric pain that may persist for several hours
before circulatory collapse. The presence ofruptured subcapsular liver
hematoma resulting in shock is an indicator for massive transfusion of
blood fresh frozen plasma and platelets as well as immediate laparotomy
(Neerhof et al., 1989) .
5. Pulmonary edema:
Pulmonary edema can have more than one etiology. First, the
pulmonary vascular hydrostatic pressure increases such as seen with left
heart failure (cardiogenic pulmonary edema). In a review often P.I.H
patients with Pulmonary edema Bendetti et al., (1985) found that the left
ventricular failure to be the cause in two ofthe patients. (20%) .
In P.I.H patients, another common mechanism involved in the
genesis of pulmonary edema is an alternation in pulmonary capillary
permeability. The most common clinical situation is the adult respiratory
distress syndrome (ARDS) or so-called " shock lung ", Haernodynamic
parameters are usually normal. Therapy usually requires intubation,
mechanical ventillation and positive end-expiratory pressure (PEEP)
(Sibai et al., 1987).
The last major etiology ofpuhnonary edema in P.I.H patients is a
reduction in colloid osmotic pressure" COP". Colloid osmotic pressure
in normal pregnancy is between 22 and 24 mmHg. In contrast, patients
with P.I.H. have demonstrated significantly lower COP values (Nguyen
et aI., 1986).
52
-.-
­1

,- -
6. HELLP syndrome:
ReviewofLiterature
Pritchard in (1978) and Weinstein (1985) reported that about 5-
10% of women with PJ.H develop the syndrome known as HELLP
where:
H =hemolysis,
EI = elevated liver enzyme
LP = low platelet count.
The syndrome is reported to be associated with a high perinatal
mortality (8-40%) and a significant maternal morbidity.
The syndrome was first reported by prithchard et al., (1954) who
explained three cases, one of whom survived, Mckay (1972) reported
four cases with two developed liver rupture and one maternal mortality.
Kitzmiller in (1974) has found the syndrome in three cases among four
patients with eclamptic thrombocytopenia. Eight cases were reported by
Goodlin et al. (1972) with perinatal mortality (44%) (Sibai, 1990) .
Redman et al., (1982) have stated that the reduced platelets is due
to increased peripheral consumption. This is supported by the bone
marrow studies that show an increase ofmegakaryocytes. Walsh (1989)
proved that the drop ofplatelet count is due to local platelet aggregation
in the utero-placental vasculature due to deficiency of prostacylin
synthesis in cells lining uteroplacental arteries.
Microangiopathic hemolytic anemia ofthe syndrome is defined as
the presence ofburr cells, chistocytes or polychromatasia on a peripheral
smear. This red cell fragmentation is considered to be due to passage
through small blood vessels that have intimal damage and fibrin deposits.
( Sibai, 1990).
At the time ofcesarian section ofpatients with HELLP syndrome,
the liver was found to have a firm consistency with occasional
subcapsular hemorrhage. Histological examination reveals small areas of
53

Review ofLiterature
hemorrhange with the adjacent liver cells showing degeneration . This
liver cell damage is responsible for the elevated liver enzymes (Neerhcf
et al., 1989) .
The only cure for HELLP syndrome is delivery and, as the nature
ofthe disease is one ofprogression, prolonged induction oflabour is to be
avoided (Sibal, 1990) . Patients who have excessive bleeding should
receive platelet transfusion either before or after delivery if the platelet
count is less than 20,000/mm . Packed RBCs may be needed ifhematocrit
value drops from continued hemolysis. There are several reports ofthe
use ofantithrombin III in treatment ofP.I.H. with HELLP syndrome. The
management is successful but more information about this approach
needs to be obtained before it can be advocated (Weinstein, 1985).
B. Remote maternal complications:
1. Recurrent PoIB :
According to Sibai, (1988), about one third ofwomen who have
had eclampsia in their first pregnancy develop P.I.H in a later pregnancy.
The prevealence of chronic hypertension in these women with recurrent
P.I.H is high and low in those without recurrence.
2. Recurrent hypertension :
P.I.H and eclampsia do not result in chronic hypertension (Chesley
and Cooper, 1986). It is found that 20 to 50% ofwomen who have
suffered from P.I.H and eclampsia become hypertensive in later years.
Women who develp P.I.H are either overt or occult hypertensive. Sooner
or later all of them will become clearly hypertensive even if they never
get pregnant. If hypertension is still present on the 10th day, the
recurrence of hypertension is 59% while 21% in women whose blood
pressure has returned to normal at that time (Browen et al., 1987).
54

II. Maternal mortality:
Review ofLiterature
Maternal mortality seems to depend upon the functional integrity
of the following organ system: renal, adrenal, cardiovascualr including
microcirculation, uterus and placenta, liver and bone marrow . Anything
which inhibits the functions ofthese organs reduces maternal homeostatic
capacity, exaggerates the experssion of the disease in progress and
decreases the chance for a successful outcome (Pritchard. 1985).
Lopez-Lieraet at, (1976) studied the factors that influence
maternal mortality and came up with the following:
1. Type ofeclampsia:
The highest mortality rate occurred in women with antepartum
eclampsia (16.9%) .
2. Age:
In a group of73 cases ofteen age eclamptic patients, the mortality
rate was 5.5% while it was 10% in another group of 89 cases who were
30 years or older (Hidaka et at, 1990).
3. Parity:
Chesley (1978) reported that a higher proportion of multiparous
have died than of women having had eclampsia as primigravidae.
Cardiovascualr cases accounted for only 29% ofthe deaths ofeclamptic
women.
4. Twillpregnancy :
The incidence of multiple pregnancy with eclampsia was about
three times that ofthe general population and the maternal mortality rate
for twin pregnancies is double the figure for the single pregnancy (7.8
versus 3.5%) (Sibai, 1986).
55

Fetal complications:
I - Fetal morbidity :
1. Fetalprematurity :
Review ofLiterature
Preterm labour may accur spontaneusly in cases of P.I.H and
eclampsia. However, it is more likely to be due to artificial induction in
the maternal interest (Ferris, 1988).
Lin et at. (1982) found that hypertensive pregnant patients of
different etiologise have three or four times more preterm deliveries than
did the non-hypertensive women.
2- Intrauterine growth retardation (IUGR):
Lin et al, (1983) found that fetal birth weight progressively
increased with increasing blood pressure range till DBP of90 mmHg was
reached above which birth weigh levelled off. They found that the
incidence of IUGR in P.l.H patients was greater in women with
prolonged hypertension (>4 weeks), heavy proteinurie (>3.5 g/24 hours)
and in multiparous women than in nulliparous women.
II. Fetal mortality:
Sibai (1988) noticed that hypertension alone in the absence of
protinuria was associated with a three fold rise in fetal death rate. The
Combination of hypertension and proteinuria had a further three fold
increase in the perinatal mortality rate. He concluded that 70% ofthe
excess deaths were due to large placental infarcts, small placental size
and abruptio placentae.
Fetal asphyxia:
The incidence offetal asphyxia was found to be increased in P.l.H
patients as compared with normal pregnant women. The average one and
the five minutes Apgar score in fetuses ofP.I.H mothers were 3 and 7
respectively compared with 9 and 9 in normal pregnancy group and this
was found to occur in 15% in women with P.I.H (Roberts et al., 1990).
56

Review ofLiterature
Management of pregnancy induced hypertension
The most effective therapy for preeclampsia is delivery ofthe fetus and
placenta in pregnancy at or near term in which the cervix is favorable
labor should be induced in addition intravenous (IV) magnesieum sulfate
(MgS04) should be used both during labor and postpartum to reduce the
risk of convulsions. Disease severity and gestational age usually govern
the decision to intervene and deliver a pareterm infant. (Abramovici and
Sibai 1999).
Mild Preeclampsia:
All patients with mild preeclampsia should receive maternal and fetal
evaluation at the time of their diagnosis .. Maternal evaluation includes
measurements of blood pressure, weight, and urine protein, and
questioning about symptoms of headache, visual disturbances and
epigastric pain. Fetal evaluation should include ultrasonography to
determine fetal growth and amniotic fluid volume, daily fetal movement
count and nonsterss testing (or biophysical profile) at least once weekly
(fig 1) (Abramovici and Sibai 1999).
Laboratory evaluation includes determination of hematocrit,
platelet counts every 2 days, and liver enzyme levels twice weekly. This
evaluation is important since patients may develop thrombyctopenia and
abnormal
elevation.
liver enzyme levels, even with minimal blood pressure
Patients are instructed to receive a regular diet with no salt restriction and
no restricted activity. Diuretics, antihypertensive drugs, and sedatives are
not used .(Sibai , 1992).
57

Introduction:
L1POROTEIN (a)
Review ofLiterature
Cholesterol and its esters, triglycerides and phosholipids are all
transported in plasma as lipoprotein particles. Free Fatty acids are
transported bound to albumin. Lipoprotein particles comprise a peripheral
envelope, consisting mainly ofphospholipids and free cholesterol (which
have both water soluble polar and lipid soluble non-polar groups) with
some apolipoproteins and a central non-polar core (mostly triglycerides
and esterified cholesterol). The molecules in the envelope are distributed
in a single in such a way that the polar groups face out towards the
surrounding plasma, while the non-polar face inwards forming the lipid
core in which the insoluble lipids are carried (Smith, 1990).
Most lipoproteins are assembled in the liver or small intestine. Five
main types oflipoprotein particles can be recognized:
1. Chylomicrons: are large particles (largest size). consisting mainly of
triglyserides 83% added to cholesterol and phosphate. They have the
lowest density. They are formed in intestinal mucosa and reach systemic
circulation via thoracic duct. They are the principle form in which dietary
triglycerides are carried to the tissues.
2. Very low density lipoproteins (YLDL): They are moderately large
particles whose main component is of neutral lipid 78% (endogenous)
added to cholesterol and phospholipid. They are mainly formed in liver
and to a lesser extent by intestinal mucosa and are secreted into plasma
from these two sites.
3. Intermediate density lipoproteins (IDL or VLDL remnants:
Arise from removal of triglycerides from VLDL during the
transition from VLDLto LDL.
4. Low-density lipoproteins (LDL): are cholesterol-rich particles,
formed from IDL by the removal of more triglyceride and apolipoprotein
A orB48 .
60
''1
.....

i-
Review ofLiterature
5. High density lipoproteins: are oftwo main types, HDL2 and HDL3.
They probably transported from peripheral cells to the liver, prior to
excrerion (Beckett, 1998).
The apolipoproteins:
The protein components ofthe lipoproteins, the apolipoproteins are
a complex family of polypeptides that promote and control the lipid
transport in plasma and uptake into tissues. They are classified into five
main groups (ape-A, B, C, E and (a)), some ofwhich may be subdivided,
and lastly apo (a).
Apo A: these are synthesized in the liver and intestine. They are initially
present in chylomicrons in lymph, but they rapidly transfer to lIDL.
Apo B: is present in plasma in two forms, apoB100 and apoB48 chyle
micron. ApaB100 is the protein component of LDL and is also present in
VLDL and LDL . ApoB100 is recognized by specific receptors in
peripheral tissues.
Apo C: is a family of three proteins (apo CI, apo ClI and apo ClII) is
synthesized in the liver and incorporated into HDL and LDL,
chylomicron.
Apo E: is synthesized in the liver, incorporated into HDL and transferred
in the circulation to chylomicrons and VLDL. There are three major
isoforrns (apoE2, apoE3 and apoE4) at a single genetic locus giving rise
to genotypes (E3/3, E2/3, E2/4, etc.).
Apo E is probably mainly involved in the hepatic intake of
chylomicron remnants and IDL,
tissues (Walker, 1990).
since it binds to apo B receptors in-the
Lipoprotein (a) "LP (a)":
The lipoprotein (a) is sixth type oflipoprotein particles. It was first
deteced in 1962. It consists of LDL particle to which a long polypeptide
chain is attached by a disulfide bridge a single apo (a) having a high
61

Review ofLiterature
carbohydrate content and having a similar amino acid sequence to
plasminogen, and is attached by a disulfide bond to the apoBl00. It is
synthesized in the liver with a poor clearance from plasma it has 11
phenotypes and 19 genotypes (Howard and pizzo, 1993).
Lp (a) is carried in plasma on a protein carrier apolipoprotein (a)
which was found to have a 90% structural homology to plasminogen.
Inheritance of apolipoprotein (a) is controlled by a specific gene on
chromosome No.6 (Wang et al., 1994).
Lipoprotein(a) LP(a) is a distinct class oflipoprotein (as shown in
table 3) that is structurally related to LDL, because both lipoprotein
classes possess one molecule ofapo B-100 per particle and have similar
lipid compositions.(Durington,1995 & Marcovina, ,1995) However
unlike LDL, Lp(a) contains a carbohydrate-rich protein apo(a) that is
covalently bound to the apo B-lOO through a disulfide linkage. The
available evidence suggest that Lp(a) contains one molecule ofapo(a) and
one molecule of apo B-IOO per Lp(a) particle (Albers, et al. 1996).
Apo(a) is the unique protein componant of Lp(a) and exhibits a
significant sequence homology with plasminogen and a high degree of
variation in polypeptide chain length. Apo(a) is composed ofa serine
protease domain and a kringle-containing domain unlike plasminogen,
however, Lp(a) is not activated to form an active protease. The kringle
that is contiguous with the protease domain, kringle 5, shares 85% amino
acid homology with plasminogen kringle 5, whereas the kringle 4 domain
has 78 to 88% amino acid homology with kringle 4 ofplasminogen.
Apo(a) contains 10 distinct classes ofkringle 4-1ike domains that differ
from each other in amino acid sequence. Kringle 4 type I and kringle 4
types3 to 10 are present as a single copy on apo(a) particles. In contrast,
kringle 4 type 2 is present in variable number ofrepeats (3 to> 40) and
62

unesterified Apoliporobein
cholesterol / Cholesteriyl Ester
~i~ure (3) Structure of a typical lipoprotein partical
Figure (4) Structure of lipoprotein (a)
K = kringle PD=Protease domain T = repeats
(Have1 and Kanc, 1995)

t-
Review ofLiterature
Table (3) Characteristics of Human plsam Lipoproteins
Vartable Chylomicron VLDL lDL lOL HDL Lp(a)
Density (glml)

Lipoprotein (a) as an atherogenic factor:
Review ofLiterature
Apolipoprotein (a) is a glycoprotein that is present in Lp(a) and has
close structural homology with plasminogen (McLean et al., 1987). Both
genes (of apolipoprotein (a) and plasminogen) are closely linked on the
long arm of chromosome 6 (Frank et al., 1988) . These give suggestive
evidence that the close homology ofLp(a) with plasminogen results in
competitive inhibition of the fibrinolytic properties of plasminogen
(Miles et al., 1989 and Harpel ct al., 1989).
Competition of Lp(a) with plasminogen for binding to endothelial
cells results in strongly down-regulated activation ofcell surface-bound
plasminogen by tissue plasmiogen activator (t-PA), suggesting that Lp(a)
may predispose to thrombotic complications (Edelberg et al., 1990).
Association of Lp(a) to different conditions:
1. Cardiovascular diseases:
The suggestion that Lp(a) might be a risk factor for cardiovascular
diseases goes back to the observations ofDahlen et al. (1972) who found
that individuals with angina pectoris exhibit an extra pre-B band In
lipoprotein electrophoresis far more frequently than the control group.
In a series of subsequent reports, attempts were make to prove the
identity of pre-B lipoprotein with Lp(a) and further to provide evidence
that Lp(a) positive individuals are at a higher risk for atherosclerosis,
cardiovascular diseases and myocardial infarction (Heiberg et at, 1974;
Dahlen et al., 1976).
It is now proved beyond doubt that Lp(a) is a potential independent
risk factor for premature cardiovascular altherogenic disease (Berg et al.,
1992).
Accumulation of Lp(a) has been found in atherosclerotic lesions
and it is now believed to be an atherogenic lipoprotein, elevated plasma
levels greater than 30 mg/dl in humans appear to be associated with an
66

+-
L"
, .-
Review ofLiterature
increased risk for the development of CAD with a rate ofoccurrence
estimated to be 2-5 times greater than in normal controls (Loscalzo,
1990).
2. Renal system :
Diseases of the kidney and their accompanying signs (proteinuria
and nephrotic syndrome) as well as end-stage renal disease and their
treatment modalities (haemodialysis, peritoneal dialysis and kidney
transplantation) have all been found to increase Lp(a) plasma levels
substantially (Bartens an Wanner, 1994).
3. Liver:
To determine the influence of liver disease on Lp(a)
concentrations, Feely et al. (1992) compared its concentrations in
patients with varying degrees of severity ofhepatic cirrhosis and patients
with established coronary heart disease they found Lp(a) concentration to
be raised in patients with coronary heart diseas and reduced in those with
cirrhosis. Concentrations tended to be lower in those with more severe
diseases.
4. Hormones:
Fluctuations III Lp(a) seem to occur in states of hormonal changes
such as in diabetes mellitus, after estrogen treatment and during
pregnancy (Bartens and Wanner, 1994).
5. Smoking:
Wersch et al.(1994) compared 68 non-smoking and 118 smoking
pregnant women with a control group of 29 subjectively healthy, age
matched non-smoking non-pregnant females. This comparison showed
significantly higher Lp(a) values during the last trimester of gestation in
non-smokers. The higher Lp(a) concentration in the plasma ofnon­
smoking women during a normal pregnancy might be a physiologic
necessity for adequate fetal growth. Lower levels ofLp(a) were seen in
67

Review ofLiterature
the last trimester ofthe smoking pregnant group, which is unfavorable for
the normal development of the rapidly growing fetus in the last stage of
the pregnancy.
Lipoprotein (a) and pregnancy:
I. Relation to normalpregnancy:
The level of serum lipids, high density lipoproteins (HDL) and
apolipoproteins are all increased in pregnancy. Serum triglycerides (TG)
and serum total cholesterol (TC) increase steadily throughout pregnancy.
In contrast serum Lp(a) levels increases until the 20th week and
reaches a value which is 1.5 times higher than the IOth week. Thereafter,
Lp(a) levels become constant until the late stage of pregnancy
(Murakami et al., 1996).
II. Relation tofetal growth retardation andfetal loss:
Berg et aI. (1994) stated that a very high Lp(a) lipoprotein level in
maternal serum during pregnancy was found to be associated with
delivery of children with low birth weight.This suggests the possibility
that a very high Lp(a) concentration may predispose to placental
insufficiency, presumably arising from pathological changes in maternal
uterine vessels in the placental bed.
They suggested that a very high Lp(a) lipoprotein level may be a
factor to consider in women who have repeated pregnancies with
placental insufficiency and who give birth to children with low birth
weight.
Such conclusion is confirmed by another study stating that elevated
Lp(a) levels occur in approximately 30% of women with recurrent
miscarriages and may have a predictive value in these women (Bauer et
aI., 1998).
68
>.

III. Lp (a) ill P.LH:
Review ofLiterature
Wang et al, (1998) demonstrated an increased plasma Lp(a) levels
in pregnant women with Preeclampisa and eclampsia in comparison to
normal pregnancy. While its level was significantly higher in severe than
in mild Preeclampisa. They concluded that Lp(a) level was associated
with the severity ofdisease and may serve as a marker ofthe pathogenic
process.
A further study was done investigating women with a history of
severe Preeclampisa and controls with a history ofnormal pregnancies
only All were tested at least 10 weeks after delivery in the second halfof
a normal menstrual cycle. None ofthe controls or patients were pregnant
or used oral contraceptives. There was no statistically significant
difference of Lp(a) level between the two groups (Van pampus et al.,
1998).
The data ofWang et al, 1998 in addition to those ofVanPampus
et a1.1998 suggest that in Preeclampisa, levels of Lp(a) increase in
relation with the severity of disease. After delivery, Lp(a) normalizes.
This suggests a specific alteration of Lp(a) level in relation to
Preeclampisa.
Hypothesis suggesting the mechanism of action of Lp(a) in
Preeclampisa (whether elevated Lp(a) is causative factor for
P reeclampisa,
In Preeclampisa, endothelial cell injury and altered endothelial cell
function appear to play a pivotal role in the genesis ofall aspects ofthe
multisystem damage, including renal and liver functions seen in
Preeclampisa (Rodgers et al., 1998). Lp(a) has been shown to induce
endothelial cell dysfunction (Hajjar et al., 1989).
A recent hypothesis was laid suggesting that genetically
determined elevated Lp(a) and its deposition in endothelial cells ofthe
69

Review ofLiterature
small vessels of placental bed initiates acute atherosis and related
thrombosis in maternal uterine spiral arteries leading to insufficient
perfusion ofthe placental bed and the clinical symptoms of Preeclampisa
(Wang et al., 1998).
A report of a family with two cases of severe Preeclampisa
/eclampsia in which very high levels ofLp(a) has been found, suggests
that a very high Lp(a) level could be one risk factor for Preeclampisa that
is genetically determined (Husby et al., 1996).
However, Dijurovic et al., (1997) made an examination of 154
women with Preeclampisa (Preeclampisa group) and 76 healthy pregnant
normotensive women (control group) .The Preeclampisa group was
further dvided into the following subgroups: mild Preeclampisa, severe
Preeclampisa and Preeclampisa with fetal growth retardation. They found
that plasma levels ofLp(a) were lower in the total Preeclamptic group as
well as in all ofthe Preeelampisa subgroups than in the control group as
determined by quantitative electroimmunoassay (Dijurovic et al., 1997).
Leerink et al. (1997) in the same year studied levels ofLp(a) and
apolipoprotein (a) phenotype in women with a history ofPreeelampisa in
a previous history (patient group) in comparison with women without
Preeclampisa in their history (control group) . They found median Lp(a)
levels in both groups to be equal as well as the apo (a) phenotype
distribution in both groups concluding. that they do not contribute
significantly to the pathogenesis ofPreeclampisa.
70

PATIENTS
AND
METHODS

Patients and Methods
Patients and Methods
This study was carried out in Obstetrics, Gynecology Department
and Biochemistry Department, Zagazig University Hospitals during the
period from October 1999 till May 2001 .
It included 60 primigravda of comparable age with single lesion
pregnancy in their 3 rd trimester and with no history of medical disease
before pregnancy such as renal disease, essential hypertension and
autoimmune disease etc.
The patients were selected from out patient clinic and obstetric
emergency unit, Zagazig University Hospitals and were classified into
three groups :
proteinuria
1st group included 20 normotensive pregnant women with negative
2 nd group included 20 pregnant women, they fulfilled the criteria of
mild preeclampsia:
• Systolic blood pressure 140 - 160 mm Hg
• Disatolic blood pressure 90 - 100 mm Hg
• Proteinuria was 1 or 2 plus by dipstick testing
3 00 group included 20 pregnant women, they fulfilled one or more
ofthe criteria ofsevere preeclampsia:
• Systolic blood pressure z 160 mm Hg
• Diastolic blood pressure z 110 mm Hg
71

..
Procedure:
Patients and Methods
1 - Dilute plasma samples with sample Buffer prior to adding to the
microtest wells. Serial dilutions were prepared as follows: 20 plasma to
1ml was added of sample buffer and mix; then add 20 ul ofthis initial
mixture to 1 ml ofsample buffer and mix; final dilution 1 : 2601.
2 - Add 50 ul ofPET Buffer to each microtest well.
3 - Add 20 ofeach Lp(a) standard (0 mg/I and 600 mg/l) to two separate
wells in duplicate. (standards was added without further dilution with
sample buffer). Add 20 ul ofeach diluted sample into a separate well. the
positions place the strips in the frame cover with a lid or plastic film.
Incubate for 60 minutes at room temperature on a micro-test plate shaker,
speed 500 pm
4 - Add 50 ul ofconjugate to each well using the 8-channel pipette .Cover
with lid or plastic film and incubate for 15 minutes at 25 CO with agitation
on a micro-test plate shaker.
5 - Empty the plate contents and wash the strips four times with PET
buffer: by filling the wells with PET buffer using a squeeze bottle, wait
for 1 minute, empty the plate and remove droplet by tapping the strips
and frame 4-5 times, face down, against absorbent material repeat do not
allow plate to dry out.
6 - Add 100 ul of substrate to each well using an 8-channel pipette or.
Start the stop watch. Incubate the strips with cover on the micro-test plate
shaker for 15 minutes at 25 C.
7 - Add 50 ul sulfuric acid to each well. Add this with the same speed and
order as you added the substrate . Agitate the plate for 5 minutes on a
micro-test plate shaker to allow complete mixing and stabilization of
color. The colored products is stable for 2 hours.
8 - Read the absorbance at 492 nm in a micro-test plate reader.
75

." '
(Table 8) Measurement against Reagent blank:
Pipette into test tubes
Reagent Blank Sample
Sample .......... 0.1 ml
Solution 1 0.5 ml 0.5 ml
Dist H2O 0.1 ml ...........
Mix, incubate for exactly 30 minutes at 37 C
Solution 2 0.5 ml 0.5 ml
Patients and Methods
Mix, allow to stand for exactly 20 min. at 20 to 25 C
Sodium. 5 ml 5 ml
Hydroxide
(0.4 MoVl)
Mix, read the absorbance of sample (Asample) against the reagent blank
after 5 minutes.
Calculation:
(Table 9) Obtain the activity of GOT in the serum from the table:
Absorbance Jl!l Absorbance Jl!l
0.020 7 0.100 36
0.030 10 0.110 41
0.040 13 0.120. 47
0.050 16 0.130 52
0.060 19 0.140 59
0.070 23 0.150 67
0.080 27 0.160 76
0.090 31 0.170 89
Determination of (SGPT) by (Retiman et al., 1957) :
u-oxoglutarate + DL-alanine GPT L-glutamate + pyruvate.
pyruvate formed is measured by monitoring the concentration ofpyruvate
hydrazone formed with 2.4-dinitrophenyl hydrazine.
79

(Table 10) Reagents:
Reagent 1 Phosphate buffer pH 7.2 100 mmolll
aPT DL- alanine 80 mmolll
Substrate 0.- ketoglutarate 4 mmol/l
Reagent 2 2.4 dinitrophenyl hydrazien 4 mmol/l
Color-reagent
Procedure.
Wavelength
Hg 546 nm
(530-550 run)
Incubation temperature: 37 C
(Table 11) Measurement against Reagent blank:
Pipette into test tubes
Reagent Blank Sample
Sample I·' .•••••• 0.1 ml
Solution 1 0.5 ml 0.5 ml
Dist H2O 0.1 ml ". '" .....
Mix, incubate for exactly 30 minutes at 37 C
Solution 2 0.5 ml 0.5 ml
Patients and Methods
Mix, allow to stand for exactly 20 min. at 20 to 25 C
Sodium. 5 mi 5 ml
Hydroxide
(0.4 Molll)
Mix, read the absorbance of sample (Asample) against the reagent blank
after 5 minutes.
80

."
(Table 12) Calculation:
Obtain the activity ofGPT in the serum from the table:
Absorbance ull Absorbance ull
0.025 4 0.275 48
0.050 8 0.300 52
0.075 12 0.325 57
O. 100 17 0.350 62
O. 125 21 0.375 67
0.150 25 0.400 72
0.175 29 0.425 77
0.200 34 0.450 83
0.225 39 0.475 88
0.250 43 0.500 94
81
Patients and Methods

Kruskal wallis test:
Statistical Analysis
A non parametric test used when the variance are not homogeneous
and it is equivalent to chi-squared.
Level ofsignificance:
For all above mentioned statistical tests done, the threshold of
significance is fixed at 5% level.
P value of> 0.05 indicates non significant.
P value of< 0.05 indicates a significant results.
P value of< 0.001 indicates a highly significant results.
85
).
"".

]RESULTS

Results
Results
This work was conducted on 60 pregnant women selected from out
patient clinic and obstetric Emergency unit of Zagazig University
Hospital.
They were classified into three groups:
proteinuria
1st group included 20 normotensive pregnant women with negative
2 nd group included 20 pregnant women, they fulfilled the criteria of
mild preeclampsia :
• Systolic blood pressure 140 - 160 mm Hg
• Disatolic blood pressure 90 - 100 mm Hg
• Proteinuria was 1 or 2 plus by dipstick testing
3 rd group included 20 pregnant women, they fulfilled one or more
ofthe criteria ofsevere preeclampsia :
• Systolic blood pressure 2': 160 mm Hg
• Diastolic blood pressure 2': 110 mm Hg
• Proteinuria 2': +++ by dipstick testing.
The serum Lp(a) level of these patients was measured using an
enzyme linked immunosorbent assay.
All the women were primigravidae of comparable age and
gestational age.
86

Results
The data was gathered and statistically analyzed and tabulated as
follows:
Table (13) Shows clinical parameters of control and study groups
Maternal age 22.6 ± 3.4 25.6 ±4.3 25.7 ± 5.1
(Years) (17.28) (16.34) (16.34)
gestational age 33.35 ± 1.8 34.5 ±2.1 33.9 ± 1.9
(Weeks) (30.36) (30-38) (28-36)
S.B.P 110.6 ± 11.5 147 ± 7.3 174.5 ± 16.05
nunHg (90-130) (140-160) (160 - 220)
D.B.P 75.5 ± 7.6 94.5 ±4.3 116.7 ± 6.1
mmHg (60 - 80) (90-100) (110 - 130)
M.ARP 83.7 ± 7.9 112.1 ±4.8 136.05 ± 9.1
mmHg (70-97) (107-120) (127.160)
From this table noticethat :
3.01 0.055 N.S
1.475 0.23 N.S
139.7 0.001 H.S
283.2 0.001 H.S
244.3 0.001 H.S
- Mean Arterial Blood pressure in normal group ranged from 70-97 mm
Hg & mean was 83.7±7.9 mm Hg.
While MABP in mild PIH ranged from 107-120 & Mean was 112.1±
4.8mm Hg and MABP in severe PIH ranged from 127-160 mm Hg &
meanwas 136.05 ± 9.1 mm Hg.
with a highly significant increase in PIH than control group.
87
.­
T
. -j

.;.
Results
Table (14) Shows biochemical parameter of control and study groups
LP(a)
mg/L
SOPT
SOOT
Uric acid
mg/dL
Serum creatinine
mg/dL
Protienuria
g/day
306.5 ± 177.5
(100-620)
9.05 ± 5.8
0-21)
9.05 ±6.7
(1-23)
4.41 ± 1.22
(2.2-6)
0.76±0.15
(0.5 - 1)
Fromthis table noticethat:
493.5 ± 156.9
(230 - 730)
14.4 ± 9.6
(4-70)
25.15 ±23.12
(2-80)
5.8 ± 0.86
(4.4 - 7)
0.81 ± 0.23
(0.5 - 1.3)
75.5 ± 34.25
(30 - 100)
573.5 ± 254.3
(270 - 955)
23.5 ± 18.95
(7 - 90)
30.55 ± 26.7
(7- 90)
6.6 ± 1.3
(4.4 - 9)
0.94 ±0.39
(0.5 - 2)
370 ± 201
(100 - 500)
9.32
4.034
5.81
18.4
2.29
5.799
- Showed the result ofLP(a) and Routin laboratory investigation.
0.001 H.S

Results
There was a significant difference was found among the studied group.
SGOT in control group was ranged from 1-23 f.! /L & mean was 9.05 ±
6.7 f.! /L while SGOT in mild PIR ranged from 2-80 J.1 /L & mean was
25.15 ± 23.12 /..l. /L and SGOT in severe Pili ranged from 7-90 J.1 /L &
mean was 30.55 ± 26.7 f.! IL.
By using F test there was a significantdifference was found in between
the studied group .
- Uric acid in normal group was ranged from 2.2-6 mg/dL& mean was
4.41± 1.22 mg/dL while in mild PIH uric acid was ranged from 4.4-7
mg/dL, mean was 5.8±0.86 mg/dL and in severe PIH uric acid ranged
from 4.4-9 mg/dL & mean was 6.6±1.3 mg/dL .
By using F. test there was a highly significant difference was found in
between the studied group .
- Serum creatinine in normal group ranged from 0.5-1mg/dL & mean was
0.76±O.l5 mg/dL while in mild PIR serum creatinine ranged from 0.5-1.3
mg/dL & mean was 0.81 ± 0.23 mg/dL & in severe PIR serumcreatinine
ranged from 0.5 - 2 mg/dL & mean was 0.94 ± 0,39 mg/dL.
By using F . test there was No significant difference in between the
studied group .
- proteinuria there was no proteinuria in normal group while proteinuria
in mild PIH ranged from 30-100& mean was 75.5±34.25 mg/dL and in
severe PIH proteinuria was ranged from 100-500 mg/dL & mean was
370±201 mg/dL.
The analysis of variance (F.test) there was a highly significant difference
ofprotienuria between mild and severe groups .
89

Results
and severe PIR (p

Control Mild PIH Severe
group PIH
(Fig.6) Histogram showing mean Lp(a) 111 control and study groups
Control Mild PIH Severe
group
PIH
/ Mean S.B.P. 1
(Fig.7) Histogram showing mean Lp(a) and mean systolic blood
pressure in control and study groups

Control Mild PIH Severe
group
PIH
I
Mean Lp(a)
Ei Mean D.B.P. 1
(Fig.8) Histogram showing mean Lp(a) and mean Diastolic blood
pressure in control and study groups
Control Mild PlH Severe
group PIH
(El Mean ~p(a) I
(Fig.9) I-iistogram showing lncatl Lp(a) and mean arterial blood
pressure in colltrol and study groups

Control Mild PIH Severe
group PIH
Q Mean Lp(a)
- - -
Results
(Fig. 10) Histogram showing mean Lp(a) and mean of SGPT in
" "
control and study groups
Control Mild PIH Severe
group
PIH
I
I
Mean Lp(a)
Mean SGOT
(Fig. 1 1 ) Histogram showing mean Lp(a) and mean of SGOT in
control and study groups

Control Mild PlH Severe
group
PIH
Results
(Fig. 12) Histogram showing mean Lp(a) and Proteinuria in control
and study groups

.,.
DISCUSSION

Discussion
Staff et al . (1999) suggested that the elevated lipid content in the
decidua basalis tissue and spiral arteries causes an acute atherosis, which
is a histologic feature of PIR. It may enhance the formation oflipid
peroxides, which are compounds that may induce endothelial dysfunction
commonly associated with the pathophysiology ofPIR .
In this study there was increase in Lp(a) level in the study b1fOUPS
compared with control !,JfOUP . This increase was significant between
control and mild PIH group (P

Discussion
uric acid unfortunately I have not found a researches which support the
previous correlation.
In this study there is a direct relationship between the elevated
Lp(a) and preeclampsia and can be used as a one of the predicator factors
for preeclampsia.
100
-{
-...

."1:.
SUMMARY
AND
CONCLUSION

-··f
Summary and Conclusions
Summary and Conclusions
PIR is a serious complication ofthe second halfofpregnancy that
occurs with a frequency of 5-15%, it is the most important form of
hypertension in pregnancy accompanied by proteinuria with or with out
edema. This disease is leading cause offetal growth retardation, infant
morbidity and maternal death (Mabie et al; 1994).
The high risk group consists of primigravida at extremes of
childbearing period «17, >35 years old) with a family history specially
the African- Americans. It accompanies most oftwin pregnancy chronic
Hypertension, diabetes mellitus and hydated form mole (Smith, 1993) .
In the placental bed, fibrin and platelet deposition, thrombosis and
infarction occurs and result in reduced placental perfusion. In severe
disease disseminated intravascular coagulation may be present with
platelet and fibrin deposition in many organs; including the brain, liver
and kidneys, altered coagulation is important in the pathogenesis ofPIH
(Roberts, 1993) •
A considerable number of tests have been introduced to predict
future occurrence of hypertension and proteinuria in pregnancy or to
diagnose specific forms ofhypertensive disease, such as PIH . Most tests
are related to one pathophysiological feature and although they may
indicate the development of particular complications such as
disseminated intravascular coagulation (DIC) ,their predictive value in
the individual patient is too low to be ofa clinical value (Collins et al:
1989)
101

Summary and Conclusions
LP(a), is a circulating lipoprotein particle which has been found to
enhance blood coagulation by compating with plasminogen for its
binding sites on fibrin clots and endothelial cells. This action is believed
to be mediated by structural homology (>90%) between apolipoprotein
(a), the carrier protein for Lp(a) and plasmenogen. The activation of
plasminogen to form plasmin is the essential step necessary for the lysis
offibrin by plasmin (Dahlen et al; 1994) .
Both in vitro and in vivo data indicate that LP(a) is involved in the
thrombotic and atherosclerotic processes that lead to a reduced blood
flow (Wang et, at; 1998) •
The aim of this work is to determine alteration ofLp(a) level in
Preeclampsia, it's predictive value and correlation with severity ofthe
disease.
This study was conducted in Zagazige University Hospitals during
the period from October 1999 till May2001 .
This work was conducted on 60 pregnant women with gestational
age ranged from 28-38 weeks divided into 2 main groups, 1st group was
20 women with Normal pregnancy (not complicated by PIH) 2nd group
comprises 40 pregnant women with preeclampsia and subdivided into 20
women with mild preeclampsia 20 women with severe preeclampsia.
Biochemical estimation ofthe level ofLP(a) was done for all the women
ofthe group, three group control, mild and sever preeclampsia.
All the data are made available about the patients considering
maternal age, gestational age, S.B.P , D.B.P, M.A.B.P, SOPT, SGOT ,
uric acid serum creatinine and proteinuria, levels ofLP(a) were tabulated
and statistically studied to detect the significance of the difference
between these data (Table 13-16) .
102
....

,.
RECOMMENDATIONS

Recommendations
Recommendations
Finally searching for LP(a) in pre-eclampsia give us a good idea
about the pathology ofthe disease, consequently it can be used as a good
indicator ofthe disease.
More work must be done to study factors that lead to production of
this dangerous fraction Determination of LP(a) in serum and arterial
blood wall must be done in other study simultaneously to help us to know
more about the pathology of the disease and to remove the contradiction
ofLp(a) levels among this studies and previous studies..
104

'W'..
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