Disusun oleh:

Hillary Clarence Danduru Rante Tondok

1261050239

Pembimbing:
dr. Maruarar Panjaitan, Sp.OG

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE

2016 Elsevier Ltd. All rights reserved
Introduction

Pre-eclampsia (PET) and intrauterine growth
restriction (IUGR) are distinct conditions they
may occur together, and are often considered
together as they share a common aetiology of
inadequate placental perfusion.

In normal pregnancy, the terminal vessels of

the maternal uterine circulation (the spiral
arteries) undergo an ordered progression of
changes from the first trimester.

Extra-villous trophoblasts migrate from the
placenta and invade and replace the
endothelium and muscular walls of the spiral
arteries supplying the placental bed.

Modified spiral arteries lose their muscular

wall, the vessel lumen becomes distended,
and the vessels become flaccid, funnel
shaped and void of vasoconstrictor ability.

Functionally, this allows large volumes of
maternal blood to pool in the intervillous
space where it surrounds the fetal vessels,
allowing transfer of oxygen and nutrients to
occur between mother and fetus

This article reviews the therapies currently in
use for the prevention and treatment of PET
and IUGR, as well as potential new therapies
currently under development.

Aspects concerning screening, diagnosis,

antenatal surveillance and timing of delivery
are beyond the scope of this review and will
not be discussed.
Case 1. Intrauterine growth
restriction therapies for
prevention

 Case 1. Intrauterine growth restriction therapies for
prevention

Miss FB , 28 years old, G2P1. Gestation 10 weeks
Her previous pregnancy : 2.1 kg baby at 36 weeks gestation.
FB requesting advice on minimising her risk of IUGR in this
pregnancy.

What prophylactic treatments will reduce FBs risk of this

pregnancy being complicated by IUGR?
1. Aspirin and antiplatelet agents

Aspirin inhibits the production of prostacyclin (a
vasodilator) and thromboxane(a vasoconstrictor). at
low doses, aspirin selectively inhibits production of
thromboxane, but not prostacyclin.

However, more recent comprehensive studies

suggest the effect of aspirin is less than first thought.
In contrast, subsequent large systematic reviews
suggest that aspirin can reduce the risk of PET and
IUGR.

A meta-analysis including over 37,000 women that
can be found 32,000 women sourced from individual
trials e concluded that antiplatelet agents reduced
preterm delivery and PET by 10%

subgroups of women suggest that the benefit of

aspirin may be limited to those who commence
therapy at or before 16 weeks gestation. These
women had a reduction in perinatal death, IUGR
and preterm birth, whereas those who commenced
prophylaxis at later gestations did not

In summary, antenatal aspirin therapy for
women who are deemed to be at increased
risk of PET or IUGR may confer a small
reduction in risk of IUGR of around 10%, and
there may be a similar sized reduction in
incidence of preeclampsia and preterm birth.
2. Anti-coagulants

This association has prompted the use of
anticoagulation as prophylaxis for these
conditions, particularly in women with a
thrombophilia.
Acquired thrombophilia

Antenatal heparin is recommended for
thrombo-prophylaxis in women with a
history of thrombus, and there is some
evidence that women with a history of
recurrent pregnancy loss have an increased
live birth rate following combination
treatment with unfractionated heparin and
aspirin.
Women with an inherited thrombophilia:

The TIPPS trial randomised 292 women with
an inherited thrombophilia, who were
deemed to be at high risk for venous
thromboembolism (VTE), PET or IUGR, to
treatment with dalteparin or to no dalteparin.
There was no difference in the primary
outcome a composite of VTE, PET, IUGR and
other morbidity e between the groups
Women without a thrombophilia

A meta-analysis of heparin alone or in
combination with anti-platelet agents in
women at high risk of developing PET or
IUGR found a reduction in birth weight less
than the 10th centile, perinatal mortality and
preterm birth before 34 and 37 weeks
gestation.
Intrauterine growth restriction e potential
new strategies for prevention or treatment

Nitric oxide (NO) is one of the most important
vasodilators in the placental circulation.

If NO production is blocked, functional impairments

in uterine artery adaptation, reduced uterine blood
flow, and smaller offspring.
L-arginine

The amino acid L-arginine is the sole precursor to
NO.

Two small, non-blinded studies of Larginine

supplementation via oral and intravenous routes
have reported significant increases in birthweight
compared to standard care.

However, a well-designed double-blinded trial failed

to show a benefit of oral arginine on fetal growth or
markers of NO production.
Sildenafil citrate

Sildenafil citrate (sildenafil) is a phosphodiesterase
inhibitor with vasodilator properties.

It is hypothesised that sildenafil may improve fetal

growth through vasodilation of the utero-placental
circulation, resulting in an increased blood flow to
the placenta.

sildenafil has been observed to produce dose

dependent vasodilation of umbilical arteries in both
pre-eclamptic and normal pregnancies.
VEGF

Vascular endothelial growth factor (VEGF) is an
angiogenic growth factor with a potent vasodilator
action that plays a significant role in virtually all
stages of placental development.

Maternal levels of VEGF are significantly lower in

IUGR pregnancies, compared to gestation matched
controls.

It is hypothesized that increasing VEGF expression

within the utero-placental circulation can improve
placental development and uteroplacental blood
flow, resulting in improved fetal growth.
Insulin-like growth factor supplementation

In late gestation, insulin-like growth factor-1 (IGF-1)
is the primary endocrine regulator of fetal growth.

In ovine studies administering IGF-1 weekly

significantly improved fetal growth compared with
saline controls
 Case 2. Preeclampsia e
therapies for prevention

 Case 2. Preeclampsia e therapies for
prevention

Name : Mrs PB
Age : 24 year old

G2P1. Her previous pregnancy was complicated by severe PET

necessitating delivery at 34 weeks gestation.
She has no other medical history and has a BP of 110/ 60 at her
12/40 booking visit.

What prophylaxis can you offer PB which will reduce the risk
of her developing PET in this pregnancy?
 Calsium

Preeclampsia Aspirin and
antioxidant e therapies for antiplatelet
prevention agents

anticoagulant
1. Calsium

One possible explanation is that low calcium
levels may increase renin and parathyroid
hormone release, leading to increased
intracellular calcium in vascular smooth
muscle, stimulating vasoconstriction.

Surprisingly, calcium supplementation

increased the risk of HELLP syndrome.
2. Aspirin and antiplatelet agents

As discussed previously, large meta-analyses
suggest that aspirin confers a 10% reduction
in risk of PET, in women with risk factors for
PET.

Significant benefit may be limited to women

who start aspirin prior to 16 weeks gestation.
3. Anticoagulants

Use of heparin was associated with a reduced
risk of hypertensive disease prior to 34
weeks, although the overall recurrence of
hypertensive disease was unchanged.
4. Antioxidants

This theory has led to the proposition that
antioxidant supplements may increase
resistance to oxidative stress, and limit the
systemic endothelial damage seen in PET.

Antioxidant vitamins are especially attractive

as a prophylaxis against preeclampsia as they
are readily available and inexpensive to
produce; of these vitamins C and E are the
most widely studied.
 Case 3. Pre-eclampsia
therapies for treatment

 Case 3. Pre-eclampsia therapies for
treatment

Name : miss PB
presents at 35 weeks gestation with headache and
visual disturbance.
BP is 160/100
Urine shows 3+ protein on dipstick.

What is the role of antihypertensive medication in

the treatment of preeclampsia?
What treatments currently available in clinical
practice can alter the clinical course of PET?
 Antihypertensive
therapy

Pre-
eclampsia
therapies for
treatment

Magnesium
(MgSO4)
Antioxidants
1. Antihypertensive therapy

Antihypertensive treatment is
instituted to minimise these risks, but
evidence that antihypertensive therapy
alters the clinical course of PET or
improves important outcomes e such as
IUGR e is lacking.
2. Antioxidants

Two randomised, double blinded, controlled
trials have treated women with severe PET
with antioxidants such as Vitamin C, E,
allopurinol and N acetyl-cysteine
 3. Magnesium (MgSO4)
In humans, MgSO4 administered intravenously improves

placental and fetal cerebral blood flow in women with mild
preeclampsia or gestational hypertension.

Current evidence is that progression from mild to severe

disease and development of serious complications related
to PET still occur despite MgSO4 use, and MgSO4 does not
prevent a majority of maternal and perinatal mortality and
morbidity related to preeclampsia.

MgSO4 will evolve from eclampsia prophylaxis to a long-

term treatment strategy in preeclampsia, due to its invasive
route of administration and the intensive monitoring which
is required to avoid toxicity.
Pre-eclampsia e potential new strategies for prevention
or treatment
Plasmaphoresis

Two case reports describe the use of plasmaphoresis to
remove free radicals or vasoactive factors from the blood of
women critically ill with preeclampsia.

L-arginine
One randomised controlled trial of -arginine in
L

combination with antioxidant vitamins demonstrated a 40%

reduction in risk of PET in women with a personal history
of PET, or a family history of PET in a first degree relative.
Treatment was begun between 14 and 32 weeks, and it is
unclear whether timing of treatment initiation or
administration of -arginine alone will have a significant
L

effect on reducing mild PET

Nitric oxide donors

There is evidence that GTN may improve
uterine and umbilical blood flow, and ex
vivo studies have shown GTN to have a
protective effect on hypoxia e reperfusion
induced apoptosis within the placenta.
A randomised controlled trial using a
higher dose (10 mg/24 hour) GTN patch in
women with gestational hypertension was
abandoned after recruiting 16 women; all
women randomised to active patches
developed severe headache within 6 hours
and withdrew from the study.
Sildenafil citrate
A recently published double-blind placebo

controlled trial found that sildenafil 150
mg/day was associated with a 4 day
prolongation of pregnancy in women with
early onset preeclampsia.
Sildenafil treatment appeared to have
other beneficial effects, including reduced
maternal blood pressure, and reduced
resistance to blood flow in the uterine and
umbilical arteries.
 Melatonin
Reduced maternal serum melatonin and placental
melatonin receptor concentrations have been

demonstrated in women with PET; these changes
may contribute to the increased oxidative stress
and resultant endothelial dysfunction observed in
preeclampsia
Animal studies have demonstrated a
neuroprotective effect of melatonin on the fetus
Statins
Statins are pharmacologic agents that inhibit 3-
hydroxy-3-methylglutaryl- coenzyme-A (HMG-
CoA) reductase known for their lipid lowering
properties and effectiveness in reducing
cardiovascular morbidity and mortality.
Hydrogen sulphide
Hydrogen sulphide is a gas produced by

both vascular endothelium and smooth
muscle which shares structural and
functional properties with NO, including
vasodilation, and a pro-angiogenic effect.
Hydrogen sulphide levels have been
shown to be reduced in maternal plasma
in women with preeclampsia, compared to
gestation matched controls.
 Conclusion

Despite causing significant morbidity, mortality and health
expenditure, PET and IUGR lack proven effective prevention
and treatment strategies which can safely prolong pregnancy
and improve outcomes.

At best, current preventative measures offer a low-modest

reduction in risk to a targeted population.

There are currently no treatments in clinical practice which can

improve intrauterine growth or alter disease progression in
PET.
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