Minimizing the Occurence and Complications of Preeclampsia:

Prevention and Prediction

Joserizal Serudji
MFU/Department of Obstetric and Gynecology M. Djamil Hospital/MF of Andalas University Padang

Introduction
Preeclampsia is a major contributor to the maternal and neonatal mortality and morbidity. It is the 2nd largest cause of maternal mortality worldwide and affects 5% to 7% of pregnant women worldwide. M.Djamil Hospital : 14,7% (2010/within 1 yr post-G30S disaster), 7,1% (2011) severe preeclampsia + eclampsia

Introduction
West Sumatera (2009): hemorrhage, Preclampsia/Eclampsia. M.Djamil Hospt (bed exps): CFR Eclampsia 10 % (2006), 30% (2007), 48 % or 10/21 (2008) 8,3% or 3/36 (2010) tim approach; neonatal mortality : ??? prematurity.

Introduction
Preeclampsia is a complex disease with multifactorial causes. To date, investigations of its prediction and prevention have not been completely successful. Clinicians do not yet have predictive and preventive standards for preeclampsia ???!!!. The prediction and prevention of preeclampsia remains a clinical issue in maternal and fetal health (Matsubara, et al, 2009) ???!!!.

Pathogenesis
The precise etiopathogenesis of preeclampsia remains to be a subject of extensive research, but it is believed that it is likely to be multifactorial. Nevertheless, it is accepted that it is the presence of the placenta rather than the fetus, which is responsible for development of preeclampsia.

 Although the placenta plays a crucial role in the development of preeclampsia, the onset, severity, and progression is significantly affected by the maternal response to placentally derived factors and proteins.

The diagram presents an overview of early trophoblast development (Huppertz, 2008)

The diagram depicts the 2 different pathways leading to preeclampsia or IUGR (Huppertz, 2008)

A schematic of placental vascular remodeling in health (upper panel) and in disease preeclampsia (lower panel) (Chesley, 2009).

PREVENTABLE?

The diagram represents the early development of the trophoblast lineage (Huppertz, 2008).

Inadequate trophoblast development vs PIH?

 Redman, (1992): the processes driving maternal systemic inflammation in pregnancy, whether normal or pre-eclamptic, must originate in the placenta, specifically from
the syncytiotrophoblast in direct contact with maternal blood, or extravillous cytotrophoblast in direct contact with decidua

central to management is delivery, which removes the causative organ, namely the placenta (Redman et al, 2006).

 It has been taken for granted that pre-eclampsia originates with deficient placentation occurring during the first half of pregnancy and this has led to the concept of a two stage disease (Redman 1991). In this model the seeds for pre-eclampsia are sown in the first half of pregnancy when full placentation fails. The disease evolves over the second half of pregnancy when the signs of pre-eclampsia, are caused directly or indirectly by increasing uteroplacental ischaemia.

2-Stage Disorder:

 There are two components that make the systemic inflammatory response abnormally intense:
an excessive placental stimulus, or an overactive maternal response to a normal placental stimulus.

These two situations are termed Placental and Maternal pre-eclampsia respectively Placental pre-eclampsia represents a disorder that is specific to pregnancy whereas maternal pre-eclampsia is specific to the woman.

 The maternal illness of pre-eclampsia was originally thought to be caused primarily by generalised maternal endothelial activation and dysfunction (Robertset al. 1989). This concept was broadened by incorporating endothelial dysfunction as one of several components of a maternal systemic inflammatory response in pre-eclampsia (Redman et al. 1999)

Endothelial dysfunction in the pathogenesis of preeclampsia (Chesley, 2009).

TRIAS ?

Pathogenesis of Preeclampsia (Lam et al, 2005)

Oxidant sources on the endothelium. In this scheme, some of the potential sources of ROS derived from the circulation or within endothelial cells are shown (Chesley, 2009)

 In placental pre-eclampsia the placenta is considered to suffer from the consequences of inadequate perfusion secondary to spiral artery dysfunction, which leads to placental hypoxia, oxidative stress and, in the most severe cases, infarction. Two abnormalities affect the spiral arteries, which are the end-arteries that supply the intervillous space: the arteries may be either too small or obstructed.

 In its purest form, maternal pre-eclampsia results from the interaction of a normal pregnancy and placenta with an abnormal maternal constitution (Redman,2006). Some medical conditions are well known to predispose to pre-eclampsia, including obesity, diabetes and chronic hypertension (tone/vasoconstriction). The decompensation from excessive systemic inflammation will happen earlier and at a lower threshold accounting for the predisposition of affected women to pre-eclampsia (Redman, 2006).

Mechanisms of insulin- mediated nitric oxide (NO) and endothelin 1 (ET-1) production leading to vasodilatation and vasoconstriction, respectively (Chesley, 2008)

Systemic inflammation in pregnancy with and without conditions that cause a chronic systemic inflammatory response (Chesley, 2009)

Trophoblast apoptosis
Normal human syncytiotrophoblast becomes apoptotic in relation to breaks in the syncytial layer (Nelson 1996). It plays a central role in turnover of cytotrophoblast and renewal of the syncytial surface of chorionic villi (Huppertz et al. 1998). Oxidative stress has been shown to induce apoptotic cell death by targeting the mitochondria directly.

 Apoptosis amounts to controlled cell fragmentation with release of subcellular microparticles in forms that are easy to clear by macrophages and other components of the reticuloendothelial system. Various types of trophoblast debris (apoptotic and non-apoptotic trophoblast fragments) that must originate in this way can be detected in the maternal circulation. Not only can such debris be detected as evidence of increased syncytiotrophoblast apoptosis but it represents one of the possible factors that may cause the maternal syndrome of the second stage of pre-eclampsia.

Risk Factors
(Matsubara et al, 2009)

Family history: mother vs mother in law = 14% : 3% NP vs MP = 64% vs 36%; RS M.Djamil (2010): 63 vs 113 (36% vs 64%) BMI >35: 4-fold greater Multiple pregnancy: twin near 4-fold Age > 40 years Diabetic vs nondiabetic: 9.9% vs 4.3 % ACA (+) Long-term semen exposure

Unadjusted probability of early preeclampsia (<37 weeks) according to body mass index (BMI) among nulliparous (N, top line) and multiparous (M, bottom line) women (Chesley, 2009)

Screening Tests
Preeclampsia is an appropriate disease to screen, as it is common, important, and increases maternal and perinatal mortality. However, although numerous screening tests for preeclampsia have been proposed over the past few decades, no test has so far been shown to appropriately screen for the disease.

Prediction
Prediction: the application of a test to asymptomatic people for the purpose of classifying them in respect to their likelihood of developing a particular disease at a later date sensitivity, specificity, predictive values. When assessing a test during pregnancy, one must also be aware that its accuracy is conditioned by the overall prevalence of the disease in the population tested. A standard method for prediction and prevention of PE has to be developed (Matsubara et al 2009)

Predictive Approach
(Matsubara et al, 2009) Classical Base theory: vascular reactivity is elevated in pregnant woman who developed PE Blood Pressure Roll Over Test (ROT) Handgrip Test (HGT) Angiotensi Sensitivity Test (AST) Doppler Ultrasound (uterine arterial blood flow) Modern Endothelial Cell Activation or Dysfunction Coagulation Cascade Imflammatory Response Angiogenic Growth Factor Cell-Free Fetal DNA in Maternal Circulation Neurokinin B Oxidative Stress

Blood Pressure
BP 16-20 weeks, gradually toward non pregnant level DBP : good predictor Risk: 8% (MAP <75 mmHg) vs 27% (MAP>85 mmHg) 2nd-TM MAP >90 mmHg: 62% sens, 82% spec; >85 mmHg: 52 and 84%

Averaged mean arterial blood pressures (W 1 SE) in women who remained normotensive throughout pregnancy (oo), in women who developed preeclampsia (**), and in women who developed hypertension (&&) by periods of 4 weeks (Chesley, 2009).

ROT
BP stimulated by a change of maternal position DBP bedrest vs DBP after the change of position (recumbent supine) (+): DBP >20 mmHg NPV: higher, reproducibility: poor

HGT
Before 15 week gestation BP changes by 3-5 min of sustained isometric exercise (+): SBP >15 mmHG during exercise or 14 mmHg immediately after exercise NPV: 98%

AST
Increase sensitiviy to AngII Dose of AngII required to 20 mmHg SBP at 26-32 weeks gestation <12 ng/kg/min: false-positive Complicated, invasive, poor PPV and NPV not considered to be an effective screening test

UABF
Fail spiral arteries remodelling utero-placental perfusion reduced UA flow reflects SA flow PI and RI RI: mean RI uterine arteries > 0,58 95% sens, 31% spec PI : >1.45 80% sens, 95% spec Arterial notch: associated with ischemic pathologic of placenta Any notch 77% sens, 85% spec; Bilateral notch 65% sens, 95% spec Reliability of PI and RI : placental position, uterine contraction, maternal heartbeat Easy and non-invasive methode Sensitivity 75 %, NPV 88%

Normal and mildly abnormal uterine artery waveforms (Hobbins, 2008)

notch

Endothelial Cell Activation or Dysfunction

Endothelial cells maintain homeostasis of : coagulation cascade, imflammatory process, and vascular tone activation or dysfunction: thrombosis, imflammation, HT Hemoconcentration: endot-dysf lead to hipertensive disorder Plasental ischemia: endot release molecules, ex. Fibronectin Plasma fibronectin conc.: significantly increased

Coagulation Cascade
APTT, PT, factor VIIIa, free protein S PAI-1/PAI-2 PlGF Serum PAI-1 level in PE and normal pregnancy 108.96 + 29.93 ng/ml and 40.67 ng/ml (p<0.05) (Defrin and Joserizal, 2006)

Imflammatory Response
In rats: TNF and proimflammatory citokin caused hypertension Serum TNF before the onset of PE soluble adhesion molecules sE-selectin and sICAM-1 in the 1st trimester TNF promotes ICAM-1 and sE-selectin activation on endoth cells and facilitates the membrane bound ICAM-1 and sE-selectin into the blood by shedding TNF activated endoth cells and promotes the expression of adhesion molecules

Imflammatory Response (contd)

Endoth activation or dysfuntion prostacyclin and NO impaired vascular relaxation Significantly of serum NO level in PE compared with normal pregnancy (Erwandi and Joserizal, 2006) Significantly maternal inflammatory response (leucocyte, neutrophyl, monocyte, kalprotectin) in PE compared with normal pregnancy (Taufiq and Joserizal, 2010)

Angiogenic Growth Factor

VEGF and PlGF: pro-angiogenic factor role in spiral artery remodelling Serum PlGF level 1st and 2nd tm, peaking early in 3rd tm before 20 weeks: in who would later develop PE Soluble fms-like tyrosine kinase 1 (sFlt-1), anti angiogenic protein in PE sFlt-1 binds with VEGF and PlGF preventing interaction with endothelial dysfunction sFlt-1 + VEGF and Pl GF 5 weeks before the onset of PE 2528 weeks + sFlt-1 957 ng/L 88% sens, 100% spec (Chesley, 2009) Simas et al (2007): sFlt- and sFlt-1/PlGF ratio are altered prior to PE onset and may be predictive of PE. sFlt-1 level was associated with hystory of PE (Roni and Joserizal, 2010)

Mean levels of sFlt1/PlGF and soluble endoglin (sEng) and by weeks before the onset of preeclampsia. (Chesley, 2009)

Cell-Free Fetal DNA

Primarily derived from placenta; is not correlated with fetal white or nucleated RBC counts, or the amount of fetal DNA Syncytiotrophoblast microparticles (including cel-free DNA and mRNA) are released from the surface of placenta into the maternal circulation Significant in the shedding of cellular debris, ie syncytiotrophoblast-microparticles (due to sincytial apoptosis caused by placental hypoxia in PE) The sensitivity and specificity:ranged between 33 and 67%, 82 and 95% (Chesley, 2009)

Neurokinin B
Biological actions: smooth muscle contraction, pain transmission, neurogenic imflammation, activation of immune system Originate mainly from the placenta Normally: can be detected in early 9th weeks gestation, in mid and late pregnancy, rapidly after delivery Markedly in PE; and so its receptor TAC3. Activation of TAC3 by neurokinin B blood flow through the liver to satisfy the needs of the uterus and placenta

Oxidative Stress
Beneficial effect of uric acid: antioxidant activity, conversly its has prooxidant activity (due to the potential of urat free radical to oxidatively modify placental protein and lipids) when other antioxidants are at low level, and stimulates the imflammatory process that lead to endothelial dysfunction. In PE: plasma concentration of uric acid at about 10 weeks preceed the clinical presentation of PE. Oxidative stress malonedialdehyde )MDA/major metabolite of lipid peroxida) endothelial cell activation In PE: antioxidant capacity, glutathione and vit C In PE: significant negative corelation between vit C intake and MDA level (Azadivon and Joserizal, 2008)

Prevention
Prevention of preeclampsia: a big disappointment (Sibai, 1996) Most studies designed on theoretical bases to reduce the incidence of preeclampsia in either low- or high-risk women have been disappointing mainly due to low sensitivity and positive-predictive value, and thus are not suitable for routine clinical use. Regimens that have been studied by randomized controlled trials
Dietary manipulations (Low-salt diet Fish oil supplementation Calcium supplementation) Cardiovascular drugs (DiureticsAntihypertensive drugs) Antioxidants (Ascorbic acid / vit C), a-Tocopherol / vit E) Antithrombotic drugs (Low-dose aspirin Aspirin/dipyridamole, Aspirin + heparin, Aspirin + ketanserin)

Prevention
Aspirin Sibai (1998): hoped-for benefit from low-dose aspirin has not been realized, and low dose aspirin might not be the wonder drug after all. Heyborne (2000): it is premature to abandon the use of low-dose aspirin therapy to pE prevention A systematic review of 14 trials using low-dose aspirin (60-150 mg/d) in women with risk factors for preeclampsia concluded that aspirin reduced the risk of preeclampsia and perinatal death, although it did not significantly affect birth weight or the risk of abruption. Low-dose aspirin in unselected nulliparous women seems to reduce the incidence of preeclampsia only slightly (Chesley, 2009). For women with risk factors for preeclampsia, starting low-dose aspirin (commonly, 1 tablet of baby aspirin per day), beginning at 12-14 weeks' gestation, is reasonable. The safety of low-dose aspirin use in the second and third trimesters is well established.

Prevention
Heparin The use of lowmolecular weight heparin in women with thrombophilia who have a history of adverse outcome has been investigated. To date, however, no data suggest that the use of heparin prophylaxis lowers the incidence of preeclampsia.

Prevention
Dietary manipulations Knuist et al. (1998): no benefits of prescribing a lowsodium intake in reducing the rate of preeclampsia (a randomized multicenter trial). In a multicenter, randomized, controlled trial, Villar et al found that at the doses used for supplementation, vitamins C and E were not associated with a reduction of preeclampsia, eclampsia, gestational hypertension, or any other maternal outcome (from Chesley, 2009). Supplementation with vit C and E during pregnancy does not prevent PE; metaanalysis ( Agudelo et al, 2011). Low birthweight, small for gestational age, and perinatal deaths were also unaffected.

Prevention
Dietary manipulations Morris et al (2001): no indication that the intake of any nutrient was related to the incidence of PE or pregnancy-associated hypertension (evidence from a large cohort study) PE prevention with calcium supplementation is unlikely to be achieved except perhaps in highrisk populations that are chronically calcium deficient(Chesley,2009, from several studies).

Hypothetic Model
Preventable ??!! Encourage patient participation Early detection Colaboration between Health Services and Religion Department:
Premarital Counceling : (+) Message card (included in Buku Nikah) greeting, guarding against signs and symptoms, prompt consultation

Selamat Berbahagia Semoga Mendapatkan Keturunan yang Sehat dan Soleh

Waspadailah kehamilan disertai preeklampsia, penyebab utama kematian ibu dan bayi; dengan gejala dan tanda:
Tekanan darah lebih dari 140/90 Adanya pembengkakan pada kaki dan tangan Sakit kepala berat Nyeri ulu hati Pandangan kabur Buang air kecil keruh

Jangan tunggu munculnya gejala dan tanda, lebih baik konsultasi dini kehamilan ke rumah sakit dengan fasilitas yang lengkap.

Padang city (Dept. of Religion): 6,996 new couples in 2010. 7 % infert : m/l 1.000 couples 6,000 PG 60% beyond 20 weeks(3,600) >250 PE/E-PG pats per year Compared to the inc. of 2010: 4 folds (250 vs 63) about to start. Plausible ???

Perspectives and Conclusions

It is evident at the present time that there is no clinically useful test to predict preeclampsia. Investigations of PE prediction and prevention have not been completely successful The prediction and prevention of PE remains a clinical issue in maternal and fetal health a really challenge in FM field!!!