PREEKLAMSI : PENYAKIT

LAMA DENGAN KONSEP

TERKINI
Johanes C. Mose

Divisi Fetomaternal Bagian Obstetri Ginekologi

FKUP/ RSHS Bandung
Kertas papyrus 2200 SM

KEJANG DAN
IBU HAMIL
KOMA MENINGGAL
IBU HAMIL EKLAMPSI MENINGGAL

Bossier de Sauvage, 1739

 PREEKLAMSI
IBU (EPH - EKLAMPSI MENINGGAL
HAMIL GESTOSIS)
 DEFINISI ?

PREDIKSI ?
ETIOLOGI ?

PATOGENESIS ?
DIAGNOSIS ?

PENCEGAHAN ?

PENGOBATAN ?

“The disease of theories”

 DEFINISI
 Ibu Hamil >20 minggu
 TRIAD gejala yang mendahului kejang dan koma (EPH
Gestosis)

1. Hipertensi

2. Edema

3. Proteinuri

 Thn 2000 : HIPERTENSI dan PROTEIN URIA

 Future……..: HIPERTENSI dan …….... ?
 DEFINISI

• 2010 – sekarang : Preeklamsi merupakan sindroma

yang ditandai oleh adanya HIPERTENSI dan
PROTEINURIA atau (dalam keadaan tanpa
Proteinuria) adanya gambaran klinis dan
laboratorium yang berat
 DIAGNOSIS
 PREEKLAMSI MURNI
 EKLAMSI
 HIPERTENSI KRONIS
 HIPERTENSI KRONIS SUPERIMPOSED
PREEKLAMSI/ EKLAMSI

 HIPERTENSI GESTASIONAL (ESENSIAL)

 GEJALA
HIPERTENSI KLINIS dan
dan HASIL
PROTEINURIA LABORATORI KEJANG
HAMIL > 20 mg MENINGGAL
UM BERAT dan KOMA
(PE) (PEB)
 PE DENGAN KOMPLIKASI
 TD : > 160/110 mmHg  TROMBOSITOPENIA(<
100.000/ul)
 SAKIT KEPALA DAN
ULUHATI YANG HEBAT  SERUM KREATININ
MENINGKAT
 GAGAL GINJAL
 SGOT/ SGPT MENINGKAT
 EDEMA PARU
 RATIO sFlt-1/ PLGF > 85
 GANGGUAN FUNGSI HATI pg/ml
 SINDROMA HELLP
 GANGGUAN VISUAL
 GANGGUAN SEREBRAL
 PJT / GAWAT JANIN
 OLIGURIA
 ETIOLOGI ?
(The disease of
theories)
• GANGGUAN INVASI TROFOBLAS

• GANGGUAN ADAPTASI IMUNOLOGIS ANTARA IBU, AYAH

(PLASENTA) , DAN JANIN

• GANGGUAN ADAPTASI IBU TERHADAPT PERUBAHAN

KARDIOVASKULER DAN INFLAMASI

• GANGGUAN GENETIK DAN EPIGENETIK

 Poor placentation- preparing the uteroplacental
blood supply for late pregnancy
NORMAL ABNORMAL

Myometrium

Before 20 weeks

Decidua

Placenta and fetus

Remodeling of spiral artery Partially remodeled spiral
to supply steady, low artery supplies pulsatile,
pressure blood flow high pressure flow
causing placental stress
Redman C. Placenta.1991;12:301–8. Redman C, Sargent I. Science 2005;308:1592–4.
VASOSPASME

INJURI
ENDOTEL
PATOGENESIS
PENINGKATAN
RESPON
PRESSOR

PROSTAGLANDIN

NITRIK
OKSIDA

ENDOTELIN

ANGIOGENIK DAN ANTI

ANGIOGENIK
 2 Stage Development of Pre-Eclampsia

STAGE 1
Poor Placentation
8–18 weeks
Predisposition to maternal disease
Maternal endothelial / Placental STAGE 2
inflammatory dysfunction Oxidative > 20 weeks
Stress
?
Typically preterm Typically term

Pre-eclampsia Pre-eclampsia
FGR
with FGR without FGR

Complications
Fetal consequence of Consequence of Maternal consequences of
placental dysfunction management: placental dysfunction
• Severe FGR • Prematurity • Cerebral haemorrhage
• Stillbirth • HELLP Syndrome
• Eclampsia
There is substantial heterogeneity in the pathophysiology
and presentation of pre-eclampsia
 Placental Pre-eclampsia:
Layers of Pathology
Diagnostic features

Primary Primary
pathology Poor placentation

Secondary Oxidatively and hydrodynamically Secondary

pathology stressed placenta
Trophoblast derived factors
eg PlGF, sFlt-1 or sEng

Maternal
Tertiary
endothelial/inflammatory Tertiary
pathology
dysfunction
Hypertension
Proteinuria

Redman C & Sargent I. Semin Nephrol. 2004;24:565-70.

 What Placental Factors Stimulate
the Maternal Signs of Pre-Eclampsia?

Oxidatively Stressed placenta

Circulating placental factors ?

Target maternal endothelium

Measurement of
Systemic inflammatory response this pathology
 sFlt-1 and sEnd
•Disrupt endothelium by inhibiting repair
•Endothelial damage causes systemic inflammation
Note that normal pregnancy is intermediate
(Redman Effect)
between non-pregnancy and pre-eclampsia

Venkatash et al 2006

What is relevance of sFlt-1 to pathogenesis of pre-eclampsia?

Pro-angiogenetic vs. Anti-angiogenetic
factors factors

Placental GF sFlt-1

Pro-angiogenesis Anti-angiogenesis
(Normal) (Preeclampsia)
POGS MIDYEAR CONVENTION 12/12/2015
19
 Rasio s-Flt-1/ PlGF

• < 38 • 38-85 • > 85

PREEKLAMSI
Hamil Normal

PREEKLAMSI BERAT
pg/ml pg/ml pg/ml
 DETEKSI DINI

• FAKTOR RISIKO
• MAP
• DOPPLER
• BIOMARKER
 PENCEGAHAN

• ASPIRIN
• KALSIUM
• ANTIOKSIDAN
• PLGF… ?
• ANTI SFLT-1…. ?
METHODS TO PREVENT PREECLAMPSIA
 ASPIRIN TREATMENT WORKS, IF STARTED EARLY

Start ≤16 weeks

PE by ~ 50% Preterm PE by89%
IUGR by ~ 55%

CUPSI 2014 12/12/2015

24
The total picture (ca. 2014) –
 Antiplatelet Agents Cochrane 2006

 51 trials, n = 36,500
 19% reduction in the risk of pre-eclampsia
 7% reduction in the risk of delivery before 37 weeks
 16% reduction in perinatal deaths
 8% reduction in risk SGA
 There were no significant differences between treatment
and control groups in any other measures of outcome
 WHO Calcium Trial among Low Calcium Intake
Pregnant Women Villar et al , SMFM 2006 Miami

 8,325 nulliparous pregnant women randomised

 < 20 weeks, populations with Ca intake < 600 mg
 1.5 g Calcium
 Severe preeclampsia RR 0.76; 0.66-0.89
 Adverse Maternal Outcome RR 0.80; 0.70-0.91
 Neonatal Death RR 0.78; 056-0.88
 Preterm Birth (women < 20yrs) 0.82;0.67-1.01
 Oxidative stress- the link between placenta and
maternal endothelium in pre-eclampsia?

 free radicals

+
 antioxidants - lipid peroxidation + free radicals

endothelial cell activation

The Vitamins In Pre-eclampsia Study

A randomised, double blind placebo controlled study of

vitamin C and vitamin E in women at increased risk of pre-eclampsia

St Thomas’ Hospital and

Chelsea and Westminster Hospital, London, UK

Chappell et al Lancet 1999;354:810-15

 Clinical outcome
25
Number of 20
women with 15
pre- Placebo
10
eclampsia Vitamins C and E
5
0
Intention- Completed
to-treat study
Adjusted 0.39 (0.17-0.90) 0.24 (0.08-0.70)
odds ratio: p=0.02 p=0.002

Chappell et al Lancet 1999

 New Developments

 PLGF or sFLt-1/PLGF ratio as triage test

 Statins

 Another anti oxidant, anti inflammation ?

 Stem cells ?
SMFM Papers www.AJOG.org
Effects of pravastatin on mediators of vascular function in a mouse model
of soluble Fms-like tyrosine kinase-1–induced preeclampsia
Karin A. Fox, MD; Monica Longo, MD, PhD; Esther Tamayo; Talar Kechichian, MS; Egle
Bytautiene, MD, PhD; Gary D. V. Hankins, MD; George R. Saade, MD; Maged M. Costantine,
MD

OBJECTIVE: We sought to investigate the mechanisms of action by which pravastatin

improves vascular reactivity in a mouse model of preeclampsia induced by overexpression of
soluble Fms-like tyrosine kinase-1 (sFlt)-1.
STUDY DESIGN: Pregnant CD-1 mice were randomly allocated to tail vein injection with
adenovirus carrying sFlt-1 or murine immunoglobulin G2 Fc (control), and thereafter to receive
pravastatin (5 mg/kg/d) or water. Mice were sacrificed at gestational day 18. Protein
expression of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor
receptor-1, and hemeoxygenase-1 were assayed by Western blot in aorta, liver, and kid- neys.
Serum total cholesterol concentrations were measured.
RESULTS: Pravastatin up-regulated eNOS expression in the aorta of sFlt-1 mice by nearly 2-
fold (P .005) to levels similar to control mice. Total cholesterol levels, vascular endothelial
growth factor receptor-1, and hemeoxygenase-1 protein expression were similar across
groups.

CONCLUSION: Pravastatin prevents vascular dysfunction in part by up- regulation of eNOS in

the vasculature. Our data support a role for statins in preeclampsia prevention.

Key words: CD-1 mouse, endothelial nitric oxide synthase, pravastatin, preeclampsia, soluble
Fms-like tyrosine kinase-1. (Am J Obstet Gynecol 2011;205:366.e1-5.)
 PENGOBATAN

• ANTI HIPERTENSI
• ANTI KEJANG
• ANTI INFLAMASI (STATIN)
• SUPPORTIF UNTUK MENGATASI
KOMPLIKASI
• TERMINASI KEHAMILAN
Effect of Magnesiaum Sulfate given for
Neuroprotection before Preterm Birth
A Randomized Controlled Trial

Caroline A. Crowther
Janet E. Hiller

Lex W. Doyle
Ross R. Haslam

JAMA 2003 ; 290: 2669-76.

RECOMMENDATIONS
( J Obstet Gynaecol Can 2011;33(5):516-529 )
The future…
The future…
 Take home messages
1. Terjadi perubahan definisi (P&E atau..)
2. Terjadi perubahan klasifikasi (PE & PEB)
3. PEAD & PEAL ( 34 minggu)
4. Rasio sFlt-1/ PlGF : Diagnosis, Pencegahan & Pengobatan
(< 38 pg/ml … >85 pg/ml)

5. MgSO4 sebagai ‘Brain Protector’

6. Pencegahan dimulai < 16 minggu (aspirin, calcium,
antioksidan, statin)

7. Antihipertensi (metil dopa, nifedipin, nicardipine)

8. Terminasi kehamilan (induksi, pervaginum atau SC)
THANK
YOU