Preeclampsia: identification of

preclinical disease and

management issues

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Outlines

1 Terminology and Diagnosis

2 Risk factors

3 Etiopathogenesis

4 Pathophysiolgy

5 Prevention and Management

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 Key Points

How pregnancy incites or aggravates hypertension

remains unsolved despite decades of intensive
research.

Hypertensive disorders complicate 5 to 10 percent

of all pregnancies

One member of the deadly triad—along with

hemorrhage and infection—that contributes greatly
to maternal morbidity and mortality

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 Terminology and Diagnosis
TABLE . Diagnostic Criteria for Pregnancy-Associated Hypertension
Gestational hypertension BP > 140/90 mmHg after 20 weeks in
previously normotensive women
Preeclampsia — Hypertension and:
Proteinuria • ≥ 300 mg/24h, or
• Protein: creatinine ratio ≥ 0.3 or
• Dipstick 1+ persistent
or
Thrombocytopenia • Platelets < 100,000/μL
Renal insufficiency • Creatinine > 1.1 mg/dL or doubling of
baseline
Liver involvement • Serum transaminase levelsc twice
normal
Cerebral symptoms • Headache, visual disturbances,
convulsions
Pulmonary edema -
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Basic Classification

1. Gestational hypertension—evidence for the

preeclampsia syndrome does not develop and
hypertension resolves by12 weeks postpartum
2. Preeclampsia and eclampsia syndrome
3. Chronic hypertension of any etiology
4. Preeclampsia superimposed on chronic
hypertension.

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Predisposing Factors
1. Age:
● > 40 years of age.
2. Obstetric history:
● Pre-eclampsia in a previous pregnancy
● Previous gestational hypertension.
● Multiple pregnancy.
● Primagravidas more common in multigravidas.
3. Preexisting conditions:
● Chronic hypertension
● Chronic renal disease
● Diabetes
● Presence of antiphospholipid antibodies or other thrombophilias
● Some congenital heart conditions.
● Obesity (Body mass index ≥ 35) at booking in.
4. Family history

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Young nulliparous vs Older multiparous

Young and nulliparous women are particularly

vulnerable to developing preeclampsia,
Whereas older women are at greater risk for
chronic hypertension with superimposed
preeclampsia
Maternal-Fetal Medicine Units (MFMU) Network
study, the incidence of preeclampsia in
Nulliparous was 5 percent in white, 9 percent in
Hispanic, and 11 percent in African-American
women (Myatt, 2012a,b).

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Obesity

It increases from 4.3 percent for women with

abody mass index (BMI) < 20 kg/m2
to 13.3 percent in those with a BMI > 35 kg/m2
(Fig. 48-5, p. 966)

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Twin

In women with a twin gestation compared with

those with singletons, the incidence of gestational
hypertension—13 versus 6 percent,
and the incidence of preeclampsia—13 versus 5
percent,
are both significantly increased (Sibai, 2000) and
The incidence is unrelated to zygosity (Maxwell,
2001).

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History of previous preeclampsia

Women with preeclampsia in the first pregnancy

are at greater risk in a second pregnancy
compared with women normotensive during their
first pregnancy (McDonald, 2009).

in the woman who was normotensive during her

first pregnancy, the incidence of preeclampsia in a
subsequent pregnancy is much lower than for a
first pregnancy.

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 Etiopathogenesis

Preeclampsia likely to develop in women with the

following characteristics:
Are exposed to chorionic villi for the first time.
Are exposed to a superabundance of chorionic
villi, as with twins or hydatidiform mole
Have preexisting conditions of endothelial cell
activation or inflammation such as diabetes or
renal or cardiovascular disease
Are genetically predisposed to hypertension
developing during pregnancy.

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Two stages of preeclampsia

Stage 1: Faulty endovascular trophoblastic

remodeling
Stage 2: Clinical syndrome

Placental vs Maternal preeclampsia

Maternal conditions include cardiovascular or renal

disease, diabetes, obesity, immunological
disorders, or hereditary influences

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 ETIOLOGY

1. Placental implantation with abnormal

trophoblastic invasion of uterine vessels
2. Immunological maladaptive tolerance between
maternal, paternal (placental), and fetal tissues
3. Maternal maladaptation to cardiovascular or
inflammatory changes of normal pregnancy
4. Genetic factors including inherited predisposing
genes and epigenetic influences.

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Abnormal Tropoblastic Invasion

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Decreased angiogenic factors: PlGF, VEGF, TGF-
beta

Increased antiangiogenic factors: sflt-1, sEng

Diminished perfusion and a hypoxic environment

eventually lead to release of placental debris or
microparticles that incite a systemic inflammatory
response

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 Immunological maladaptation

 Formation of blocking antibodies to placental antigenic

sites might be impaired
 Women previously exposed to paternal antigens,
such as a prior pregnancy with the same partner, are
“immunized” against preeclampsia
 Molar pregnancy with doubled paternal chromosom
 Reduced amounts of immunosuppressive nonclassic HLA
G.
 Increased TH1, decreased TH2, promote inflammatory
reaction are stimulated by placental microparticles

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 Endothelial Cell Activation

 Response to placental factors released by ischemic

changes or by any other inciting cause, a cascade of
events begins: activating TNF alfa, IL, free radicals
 Generate highly toxic radicals that injure endothelial cells,
modify their nitric oxide production, and interfere with
prostaglandin balance.
 Production of the lipid-laden macrophage foam cells seen
in atherosis
 Activation of microvascular coagulation manifest by
thrombocytopenia; and increased capillary permeability
manifest by edema and proteinuria.

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Endotelial cell injury

Protezela and colleagues (2012) demonstrated

increased levels of circulating endothelial
microparticles—EMPs—in preeclamptic women.
Decreased PGI2 increased Tromboxane A2
Increased sensitivity to angiotensin II –
vasoconstriction
Decreased level of NO as potent vasodilator

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Genetic Factor

Preeclampsia is multifactorial, polygenic disorder

Ward and Taylor (2014) cite an incident risk for
preeclampsia of 20 to 40 percent for daughters of
preeclamptic mothers; 11 to 37 percent for sisters
of preeclamptic women; and 22 to 47 percent for
twins.
Hereditary predisposition for preeclampsia likely is
theresult of interactions of literally hundreds of
inherited genes—both maternal and paternal—that
control myriad enzymatic and metabolic functions
throughout every organ system.
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Candidate Genes

MTHFR, F5 leiden, AGT, HLA, NOS3, F2, ACE,

CTLA4, LPL, SERPIN2 (positif significant
correlation)
Fas receptor, hypoxia-inducible factor-1α protein
(HIF-1α), IL-1β, lymphotoxin-α, transforming
growth factor, beta 3 (TGF-β3), apolipoprotein E
(ApoE), and TNF-α (Varying result)

Preeclampsia syndrom is a complex phenotypic

expression, it is doubtful that any one candidate
gene will be found responsible.
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 endothelial
widespread Patofisiologi
dysfunction and
coagulopathy

Generalized Coagulo
.

vasospasm Widespread pathy

resulting in
hypertension and increase in primarily
manifests as a
organ damage due to vascular trombocytope
hypoxia, especially of
the brain, liver permeability nia severe DIC
and kidneys. or the HELLP
Edema syndrome.
Reduced
Intravascular Volume

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 Severity level
Abnormality Non severe Severe
Diastolic < 110 mm Hg ≥ 110 mm Hg
Systolic < 160 mm Hg ≥ 160 mm Hg
Proteinuriac None to positive None to positive
Headache Absent Present
Visual disturbances Absent Present
Upper abdominal Absent Present
Oliguria Absent Present
Convulsion Absent Present
Serum creatinine Normal Elevated
Serum transaminase Elevation Minimal Marked
Fetal-growth Restriction Absent Obvious
Pulmonary Edema Absent Present

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 PREVENTION
Some Methods to Prevent Preeclampsia That
Have Been Evaluated in Randomized Trials

Dietary manipulation—low-salt diet, calcium or fish oil

supplementation
Exercise—physical activity, stretching
Cardiovascular drugs — diuretics, antihypertensive drugs
Antioxidants — ascorbic acid (vitamin C), α-tocopherol
(vitamin E), vitamin D
Antithrombotic drugs — low-dose aspirin, aspirin/
dipyridamole, aspirin + heparin, aspirin + ketanserin

Modified from Staff, 2014.

 none of these has been found to be convincingly and reproducibly

effective.

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 Low Dose Aspirin for High Risk
Maternal-Fetal Medicine Units Network
Trial of Low-Dose Aspirin in Women at
High Risk for Preeclampsia
No PE % PE %
Normotensive, no proteinuria 1613 14.5 17.7
Proteinuria plus hypertension 119 31.7 22.0
Proteinuria only 48 25.0 33.3
Hypertension only 723 24.8 25.0
Insulin-dependent diabetes 462 18.3 21.6
Chronic hypertension 763 26.0 24.6
Multifetal gestation 678 11.5 15.9
Previous preeclampsia 600 16.7 19.0

No statistically significant difference for any comparison

between groups.
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Aspirin

Although there were no benefits to low-dose

aspirin, the accompanying metaanalysis reported
a lowering of risk.
The 2013 Task Force recommended the use of
low-dose aspirin in some high-risk women to
prevent preeclampsia.

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Management of preeclampsia

The basic management objectives for any

pregnancy complicated by preeclampsia are:

(1) termination of pregnancy with the least possible

trauma to mother and fetus,
(2) birth of an infant who subsequently thrives,
(3) complete restoration of health to the mother

 important clinical questions for successful

management is precise knowledge of fetal age
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