PREDICTION AND PREVENTION OF PREECLAMPSIA

Ruchika GargAssistant Professor

Dept of Obstetrics and Gynecology

SN Medical College,Agra

RUCHIKA GARGASSISTANT PROFESSORDEPT OF OBSTETRICS GYNECOLOGYSN MEDICAL COLLEGE,AGRA

Assistant Editor JSAFOGAssistant Editor JSAFOMS

PREECLAMPSIA DISEASE OF THEORIES

Inflammation Immunological Prostaglandin imbalance Angiogenic factors Toxins Malnutrition Vitamin Deficiency Stress

Screening by Maternal HistoryRates of preeclampsia depend on: severity of underlying complications& combinations of risk factors. Risk% Risk factors

15-40 Chronic hypertension/renal disease10-35 Pre gestational DM10-20 Connective tissue disease (lupus, rheumatoid

arthritis) 10-40 Thrombophilia (acquired or congenital) 10-15 Obesity/insulin resistance 10-20 Age older than 40 y10-35 Limited sperm exposure10-15 Family history of preeclampsia/ cardiovascular

disease1.5 fold Woman born as SFGA

2-3 fold

Adverse outcome in a previous pregnancy: IUGR, abruptio placentae, IUFD

In PE: Impaired trophoblast differentiation & invasion

SCREENING TESTS FOR PE (WHO, 2004)I. Placental perfusion & vascular resistance dysfunctionMean arterial blood pressureRoll over test Doppler ultrasound Isometric exercise test Intravenous infusion of angiotensin II Platelet angiotensin II binding Platelet calcium response to arginine vasopressin Renin 24-hour ambulatory blood pressure monitoring

FETOPLACENTAL UNIT DYSFUNCTION

• Human chorionic gonadotropin

• Alpha fetoprotein

• Estriol • Inhibin A

• Pregnancy-associated plasma protein A

• Activin A • Corticotropin

release hormone

III. Renal dysfunction

Serum uric acid Microalbuminuria Urinary calcium excretion Urinary kallikrein

Microtransferrinuria

N-acetyl- glucosarninidase

ENDOTHELIAL & OXIDANT STRESS DYSFUNCTION , 1. Platelet count2. Platelet activation

and endothelial cell adhesion molecules

3. Prostacyclin4. Cytokines5. Isoprostanes, 6. Antiphospholipid

antibodies

•Fibronectin •Endothelin •Thromboxane •Homocysteine •Serum lipids• Insulin resistance •Plasminogen activator inhibitor •Leptin •Total proteins •Magnesium •Ferritin •Haptoglobin •microglobulin •Genetic marker

IDEAL BIOCHEMICAL MARKER Play a central role in the pathogenesis

and be specific for the condition. Appear early or before the clinical

manifestations. Placental factors that can be detected

early in pregnancy are likely to be good biochemical markers for PE prediction.

HYPERURICAEMIA Correlates with clinical severity of

preeclampsia and perinatal outcomes.

Despite a good amount of studies, not of all studies suggest that the serum uric acid levels may begin to rise before the onset of hypertension and proteinuria.

an early sign of renal involvement in preeclampsia- ↓↓ renal clearance due to altered tubular processing of uric acid preceding glomerular affliction.

the discriminatory value of serum uric acid as a predictor of preeclampsia remains to be proven

ANGIOTENSIN II SENSITIVITY

.

Recent study- sensitivity of 22%

specificity of 85% for prediction of PE. The disappointing results of recent studies raises doubts about usefulness as a continuing test.

I. BiophysicalMean arterial pressure

•Better predictor of PE than S& D BP (BMJ 200817;336:111; Meta-analysis of 34 RCT)

2nd trimester MA BP ≥ 90 mm Hg had +ve LR 3.5 and –ve LR 0.46

•BP remains the cornerstone of early diagnosis although it has limitations:measurement errors associated with sphygmomanometereffect of maternal posture on BP in pregnant women.

LOW CALCIUM/CREATININE RATIO AND HIGH MICROALBUMINURIA

• 84% developed PE. • Microproteinuria > 375mg/l may be significant •Could be utilized as a screening test for the early detection of a woman at risk of developing preeclampsia. •There is no diagnostic value of microalbuminuria and the calcium/creatinine ratio when used alone.

CYSTATIN C

Suggested as a predictive first trimester marker for PE .

Given the low screening performance of the study, cystatin C is probably not clinically useful as a single marker but could be useful in combination with other biochemical markers.

PROTEOMICS ALTERATIONS IN PRE-ECLAMPSIA Suggest that possible cellular battle

against mitochondria-originated oxidative stress test resulting in recovery or apoptosis.

The over expression of chaperonin 60, GST, VDAC, Erp29 and cathespin D in

PE makes it a ideal marker of predicting preeclampsia .

Women with PE present a unique urine proteomic fingerprint composed of SERPINA1 and albumin fragments that predicts PE in need of mandated delivery with highest accuracy.

To distinguish preeclampsia from other

hypertensive or proteinuric disorders in pregnancy.

Cell free DNA is a promising new marker.

Increased before the onset of disease

Int j Mol Sci 2015

Urinary excretion of N-acetyl-beta- glucosaminidine, a lysosomal enzyme of the renal tubular cells ↑↑↑ in normal pregnant women and in woman with transient hypertension Vs non pregnant healthy controls.

In PE, the increase was much higher than corresponding to their gestational age

SERUM THROMBOMODULIN ANTIGEN LEVELS Pre-eclampsia Vs gestational

hypertension or chronic hypertension.

↑↑↑Thrombomodulin may serve as a clinical marker to differentiate preeclampsia from other disorders of pregnancy.

SCREENING DOWN SYNDROME

•in the first trimester is a example where a combination of ultrasound and biochemical markers are used. • Measurement of other indices with inhibin A can produce a test with greater sensitivity for PE as occurs with triple or quadruple blood tests for Down's syndrome ?

Inhibin A is the best predictor of Pre-eclampsia out of unconjugated estriol,beta hcg at second Trimester.

A more sensitive marker for the prediction of preeclampsia than hCG.

hCG + inhibin did not improve the screening efficiency for preeclampsia

suggesting that inhibin-A and hCG are markers of the same underlying pathological process

Fetal Diag Therapy 2011

Midtrimester beta-hCG levels alone correlated significantly with the severity of preeclampsia.

Combination of Maternal Serum hCG levels, BMI,parity and age as a predictive test for preeclampsia was far superior to hCG alone.

Sensitivity of 70% , Specificity of 71 %.

Serum levels of collagen synthesis, procollagen I, carboxy- terminal peptide (PICP) and procollagen111 amino-terminal peptide (PIIIP), in patients with preeclampsia and controls.

The markers were mildly elevated in preeclampsia, but unlikely to be useful in the prediction of preeclampsia

Preeclampsia is a 2 stage disorderStage 1

Invasion of Spiral Arteries into myometrium is inadequate.Stage 2 in

late pregnancy

Oxidatively stressed placenta releases antiangiogenic proteins

Tyrosine kinase 1 ,PGs and Cytokines.Hypoxic placenta

reduces the production of pro angiogenic factors –Placental

Growth Factor PIGF,VEGF

PREGNANCY – ASSOCIATED PROTEIN PAPP-A Glycoprotein synthesized in the

placenta Maternal plasma conc. increases

through out pregnancy. PAPP-A ,b-hCG and nuchal translucency

thickness, to screen for trisomy 21, 13 and 18 at 11 to 13 weeks GA.

In fetuses with normal chromosomes ↓ PAPP-A in 1st trimes - ↑↑↑ risk for PE, IUGR, SGA and preterm delivery

PAPP-A when used as a single biochemical marker,

is only about 10 to 20 % Sensitive. Combined with Doppler ultrasound, PAPP-

A is a powerful predictive biochemical marker of PE

prediction rates of 70% at false positive rates of 5%.

At term, plasma PAPP-A have been shown to increase in pregnancies complicated by PE and HELLP, but its concentration is still not predictive

PLACENTAL PROTEIN 13 ,PP13 a member of the galectin family produced by the placental trophoblast

cells and is associated with normal placentation.

In normal pregnancies, serum PP13 slowly rise with GA. ↓↓ levels in the first trimester in pregnancies that subsequently develop PE.

+

Serum screening + Doppler ultrasound pulsatility index (PI), Prediction rate 71% at a false positive 10%

PP13 was concluded to be a reasonable biochemical marker for early onset and preterm PE but a weak marker for PE at term

Endoglin is homodimeric transmembrane glycoprotein .

ELEVATED SOLUBLE FMS-LIKE TYROSINE KINASE 1 (SFLT-1) OCCUR BEFORE THE CLINICAL SYMPTOMS

The levels correlate with the time of onset of clinically manifest PE and partly with disease severity.

Early-onset PE exhibits higher levels of sFlt

↑↑ is observed ~5 weeks before onset of PE

AS A FIRST TRIMESTER SCREENING MARKER. .

soluble endoglin (s-Eng) . sEng+ Doppler ultrasound (PI) and PlGF, the prediction rate for early onset PE was 77.8% at a false positive rate of 5%

sFlt-1 levels are stable during early & mid gestation ,then

increase significantly during late stages

11-13 WEEKS

Maternal plasma sEng and Uterine artery PI are ↑↑.PIGF and PAPP-A are ↓

Uterine Artery PI was ↑↑ .but no significant difference in the maternal plasma conc.of sEng or sPAPP-A

Late PE

CIRCULATING ANGIOGENIC FACTORS AS PREDICTORS OF PE

.

Low increase in PlGF in early pregnancy ,independent of change in sFlt-1 is associated with high risk –PE.

Low or no ↑↑ in serum free PlGF , VEGF & high conc. of sFlt-1 a strong predictor of early PE.

Low increase in PlGF & low ↑↑ in sFlt are associated with 10 fold higher risk of pre term

PE

In the unaffected group, multiple regression analysis - at

30-33 weeks serum sEng for third-trimester log10 sEng was significantly lower in women of

Afro-Caribbean racial origin than in Caucasians ,

higher in nulliparous than in parous women.

Consequently sEng must be adjusted for these variables

before comparing with pathological pregnancies

Higher sEng in women developing PE and the inverse relation between the level of

sEng and GA at delivery for PE is compatible with the role of this anti-

angiogenic factor in inducing vascular endothelial cell injury and dysfunction before the clinical onset of the disease

sEng+ Doppler ultrasound (PI) and PlGF, the prediction rate for early onset PE was 77.8% at a FP rate of 5%

As a single biochemical marker, PlGF has been shown to predict 53.5% of early onset PE at a false positive rate of 5%

at a false positive rate of 10% in late first trimester.

PlGF could be a promising biochemical marker even in the first trimester particularly if combined with HbF and A1M.

Increase in sFlt -1 ,↓PIGF and VEGF . sFlt-1 soluble vascular endothelial growth factor

receptor-1

69 (60 - 77)

0 20 40 60 80 100

Doppler combinations of FVWDoppler resistance indexDoppler pulsatility indexDoppler other ratiosDoppler bilateral notchingDoppler any/unilateral notchingSDS Page proteinuria 100 (88 - 100)Kallikreinuria

Microalbumin/creatinine ratioMicroalbuminuriaTotal albuminuria

Total proteinuriaUrinary calcium/creatinine ratioUrinary calcium excretionSerum uric acidOestriolHCGFoetal DNA

Fibronectin totalFibronectin cellular

AFPBMI<19.8BMI>24.2BMI>29

0 20 40 60 80 100

BMI>34

2529882119111224645316332127982

2289679821469726192933114345153307142219088

22281345705514

2681172732351373135

13709715272044021441082316200

11 (8 - 16)41 (29 - 53)23 (15 - 33)18 (15 - 21)

64 (54 - 74)66 (54 - 76)48 (29 - 69)55 (37 - 72)48 (34 - 62)63 (51 - 74)

19 (12 - 28)62 (23 - 90)70 (45 - 87)35 (13 - 68)50 (36 - 64)57 (24 - 84)36 (22 - 53)26 (9 - 56)24 (16 - 35)50 (31 - 69)65 (42 - 83)50 (30 - 70)9 (5 - 16)

83 (52 - 98)

80 (73 - 86) 75 (62 - 84)88 (80 - 93)93 (87 - 97)

86 (82 - 90)

80 (74 - 85)87 (75 - 94)80 (73 - 86)92 (87 - 95)82 (74 - 87)

75 (73 - 77)68 (57 - 77)89 (79 - 94)89 (79 - 94)80 (66 - 89)74 (69 - 79)83 (73 - 90)82 (61 - 93)89 (86 - 92)88 (80 - 93)

94 (86 - 98)96 (79 - 99)96 (94 - 98)

98 (98 - 100)

Sensitivity Specificity

Sn (95% CI)Test No of studies No of women Sp (95% CI)

Prediction of preeclampsiaMethods of prediction and prevention of pre-eclampsia: systematic reviews ofaccuracy and effectiveness literature with economic modelling CA Meads, et al 2008

0.01 0.1 0.2 0.5 1 2 5 10

Progesterone 0.21 (0.03, 1.77)

Nitric oxide donors and precursors 0.83 (0.49, 1.41)

Diuretics 0.68 (0.45, 1.03)

Antiplatelets 0.81 (0.75, 0.88)

Antihypertensives v none 0.99 (0.84, 1.18)

Marine oils 0.86 (0.59, 1.27)

Magnesium 0.87 (0.57, 1.32)

Garlic 0.78 (0.31, 1.93)

Energy/protein restriction 1.13 (0.59, 2.18)

Isocaloric balanced protein supplementation 1.00 (0.57, 1.75)

Balanced protein/energy intake 1.20 (0.77, 1.89)

Nutritional advice 0.98 (0.42, 1.88)

Calcium 0.48 (0.33, 0.69)

Antioxidants 0.61 (0.50, 0.75)

Altered dietary salt 1.11 (0.46, 2.66)

Rest alone for normal BP 0.05 (0.00, 0.83)

Exercise 0.31 (0.01, 7.09)

Bed rest for high BP 0.98 (0.80, 1.20)

Ambulatory BP

1

4

4

43

19

4

2

1

2

1

3

1

12

7

2

1

2

1

0

128

170

1391

33439

2402

1683

474

100

284

782

512

136

15206

6082

631

32

45

228

0

Relative Risk (95% Confidence Interval)

RR (95% CI)Intervention No of RCTs No of women

Primary Prevention Of PE

Uterine artery Doppler ultrasoundImpaired trophoblastic invasion of the spiral arteries: reduction in uteroplacental blood flow}•High pulsatility index and/or Notch in 1st & 2nd trimesters: poor predictor of PE(Papgeorghiou & Leslie, 2007)

Uterine artery Doppler plus biochemical markers•Promising results •Current data do not support this combination for routine screening for PE (Barton& Sibai, 2008).

Early-onset preeclampsia(<34 wks’)

Late-onset preeclampsia(<34 wks’)

Recurrent preeclampsia

Effective available

Maternal variables+maternal MAP+uterine artery Doppler+PAPP-A and PIGF in First trimester yielded 94.1% sen and 94.3%spec(FPR5%)(Poon et al.2009)

Poor prediction (35.7%) From Poon’s model

By history alone,overall recurrence is 14.7% <

25wks’:38.6%

29-32 wks’:29.1%

33-36 wks’: 21.9%

≤ 37 wks’:12.9%

(Mostello et al.2008)

Reduce maternal,perinatal morbidities

To be proven Screening may not significantly reduce morbidities

Aspirin 75mg/D started after 12wks’(NICE 2011)

Pointing to “specific” prevention

To be proven(ASA?)

To be proven No

Clinical examination

Sensitivity Specificity

Body mass index (BMI)

BMI ≥ 25 47%(33-61) 73%(64-83)BMI ≥ 30 19%(19-20) 90%(88-93)BMI ≥ 35 21%(12-31) 92%(89-95)

Blood pressure in the first trimester

Mean arterial pressure

≥90mmHg

62%(35.89) 82%(72-92)

Hemodynamic investigations

Uterine artery doppler in

second trimesterHigh PI and

notching in low-risk

23%(14-35) 99%(98-99)

High PI and notching in high-

risk

83%(36-100) 96%(90-99)

Unilateral notching

19%(5-42) 99%(97-100)

HBF AND A1M HbF and A1M play a role in the

pathophysiology of PE . The biochemical markers appear as early

as 10 weeks of gestation . can be measured with basic ELISA

techniques and show a high prediction rate at a low false positive level.

Serum HbF and A1M ↑↑ at 10 to 16 weeks’ who subsequently developed PE. HbF and adult hemoglobin (HbA) significantly correlated to maternal BP in patients with established PE

Maternal plasma free HbF correlate well with severity, i.e. blood pressure, in term PE pregnancies .

PLASMA AND TISSUE PROTEIN A1M

bind and degrade heme Free radical-scavenger properties , protect

tissues against extracellular Hb, heme and ROS .

Pathogenic role of Hb and protective role of A1M in PE is supported by placenta perfusion experiments .

Maternal serum HbF and A1M- predictive and diagnostic markers for PE, have shown promising results .

'GENES FOR PRE-ECLAMPSIA' DISCOVERED The genes on which the errors were

identified (MCP factor I and factor H) play a role in regulating immune response .

This could explain their possible link to PE

Women with lupus and other autoimmune diseases - in the study - ↑↑ed risk of PE.

HOMOCYSTEINE

Not a Predictive Marker

Biomarker 1st trim 2nd trim Symptomatic Combination Also correlated

withPAPP-A ↓ ↓ ↓ SGAPP-13 ↓ ↑ ↑ US UIGR,prete

rmFdna ↑ ↑ ↑ Inhibin-A IUGR,

polydramios trisomy

21,18 preterm

DNA ↑SFlt-1 ↑ ↑ sEng, PIGF,

VEGF, US

PIGF ↓ ↓ ↓ sEng,sFit-1 SGAsEng ↑ ↑ sFit-1,PIGF,US IUGR,

HELLPP-selectin ↑ ↑ ↑ Activin A,sFit-

1PTX-3 ↑ ↑ ↑ IUGR

Summary of Potential Serum Biomarkers for Prediction of Preeclampsia

There is no proven effective method for prevention of Preeclampsia

Pharmacological prophylaxis

Nutritional supplement

Lifestyle intervention and

diet Antiplatelet

agents Nitric oxide

agents Low-

molecular weight heparin

Antihypertensives for mild and moderate hypertension

Progesterone Diuretics

Calcium Antioxidant Folic acid Magnesium Marine oil and

prostaglandin precursors

Rest Exercise Altered

dietary salt Energy and

protein intake Garlic

CAN COMBINED SCREENING LEAD TO TRAGETED PREVENTATIVE THERAPY?Treatments evaluated for preeclampsia prevention

Aspirin Largely ineffective, except in

subgroup of “clinically” high-risk women

Nitric oxide donors Ineffective

Diuretics ineffective

Progesterone ineffective

Low-molecular weight

heparin

Largely ineffective, except in small subgroup of thrombophiliac

Recombinant investigational

Calcium Largely ineffective,

except in setting of low dietary calcium intake

(<600 mg/day or corresponding to less

than two dairy servings per day)

Magnesium Ineffective

Folic Acid Ineffective

Antioxidants (vitamin

C&E)

Ineffective

Efficacy of medications proposed to prevent preeclampsiaEfficacy of dietary supplements proposed to prevent preeclampsia

Folic 0.46(0.16-1.31)

Magnesium 0.87(0.57-1.32)

Marine oil 0.86(0.59-1.27)

Lifestyle

interventions

Rest 0.05(0-0.83)

Exercise 0.31(0.01-7.09)

Altered dietary 1.11(0.46-2.66)

Energy and protein

intake

1.2(0.77-1.89)

Garlic 0.78(0.31-1.93)

Intervention RR(95% CI

Pharmacologic

Anti-platelets 0.90(0.84-0.97)

Nitric oxide 0.83(0.49-1.41)

Low-malecular weight

heparin

0.23(0.08-0.68)

Antihypertensives 0.97(0.83-0.68)

Progesterone 0.21(0.03-1.77)

Diuretics 0.68(0.45-1.03)

At 11-13 weeks aim for early prediction of early PE

BECAUSE PREVALENCE CAN BE POTENTIALLY REDUCED BY THE PROPHYLACTIC USE OF LOW-DOSE ASPIRIN (started before

16 weeks Gestation

QUESTIONS TO BE ADDRESSED What are the cut-offs? Gestational age specific? sFlt-

1/PIGF or PIGF/sFlt-1 ratio? When to start the testing, and at what interval? Preeclampsia is a heterogeneous disease. The

disease with an earlier onset (<32 Weeks’) is more homogeneous and more predictable.

Incorporation into first or second trimester selecting for fetal Down syndrome? Genetic susceptibility must be taken into account.

Expectant management of second preeclampsia (prediction of disease progression)?

Can serum antigenic peptides help selecting suitable candidate and predict the perinatal outcomes?

CONCLUSION

There is no clinically useful test to predict Pre-eclampsia at present

Care must be given to cost effectiveness and applicability to general practise

When U know something, to hold that you know it & when U don’t know something, to allow that you don’t know it, that is Knowledge

Confucius ( 55BC – 479 BC)

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