Clinical significance of the uterine artery Doppler flowmetry :

state of the art

Campbell S et al: New Dopplertechnique for assessinguteroplacental blood flow. Lancet 1983; 1: 675-677

Significance of pre-eclampsia (PE)

* Incidence of 3-14% worldwide* Accounts for 100.000 maternal deaths worldwide per year* Second most common cause of maternal death in the developing world*Principal cause of maternal admission to ICU* Causes 4-fold increase in perinatal mortality* Responsible for 10% of stillbirths and 15% of preterm births* Causes long term maternal and infant morbidity RCOG Maternal Mortality Report 2008

Perinatal mortality

Fetal abnormalitiesPremature birthImpaired placentation

Account for more than 90 % of perinatal deaths

Aetiological factors in PE

*Inadequately modelled spiral arteries ( impaired trophoblastic invasion )* Restriction of placental perfusion (hypoxemia in placental bed )* Early placental ischaemia* Up-regulation of anti- angiogenesis factors(endoglyn and sflt-1) * Down-regulation of angiogenic factors (VEGF, PIGF )* Increase in oxygen free radicals* Widespread maternal vascular endothelial dysfunction* Reduced vascular endothelial nitric oxide production (key factor in symptomatology of PE )* Generalised vasoconstriction

KEY vessel

for prediction of pre-eclampsia

UTERINE ARTERY

Uterine artery Doppler

Quality assurance :

* Angle of insonation : always < 45 degrees* Sampling gate size : 2 mm* Main uterine artery ( not branches )* 1 cm above the crossing site * No compression of uterine artery by transducer

Predictive Values with/without notches for all complicationsHarrington K et al UOG 1996

Sensiti-vity (%)

Specifi-city (%)

PPV (%)

NPV (%)

Any notchAny complications *Severe complications **

5154

7674

3213

8896

Bilateral NotchesAny ComplicationSevere complications

3176

9193

4347

8698

No notch/Mean RI > 90th

Any complicationSevere complications

2439

9291

4019

8595

* Any complication: PPIH, SGA <10th, placental abruption, stillbirth/NND** Severe complications: PPIH prior to 37 wks, SGA < 3rd, plac.abruption, still birth

DOWN’S SYNDROME PRE-ECLAMPSIA

Prevalence 1:600 Prevalence Severe (Del. < 34 wks): 1:200Very severe ( Del. <32 wks): 1:300

Triple Test UTA Doppler

Sensitivity (15 w): 60% Severe Very severeSensitivity (14 w) 40% 60 % (23 w) 77% 93%

False Positive Rate = 5%Martin 2001, Papageorghiou 2001

The future :

First trimester screening for PE

Early biomarkers to predict PE

* Angiogenic proteins : VEGF, PIGF* Anti-angiogenic proteins : SFLT 1, s-Endoglyn * PAPP-A* PP 13* Inhibin A , Activin A

Sensitivity for Predicting early onset PE with different FPR using BCH markers and UTAPI

Markers FPR 1 % FPR 2% FPR 5% FPR 10%

Early onset PEPP13PIGFMAPUTAPI

34313740

44414751

58556267

69677479

MAP & UTAPI 59 70 83 91

PAPP-A, MAP & UTAPI

64 74 86 93

PP13, PAPP-A, MAP & UTAPI

71 80 88 94

PIGF, PAPP-A, MAP & UTAPI

74 83 92 97

8366 women; 165 PE (20%); 37 early onset PE (0.4%).K. Nicolaides Data ( Cuckle, UOG 2011)

Prevention of Pre-eclampsia

UTA Doppler as non-invasive tool for monitoring of therapeutical effect in PE

Agents that have been tried :

HeparinLow-dose Aspirin Nitric oxide SteroidsFish oilAntioxidants(vit. E)MagnesiumCalcium

Yellow = some benefit Red = potentially dangerous

Low dose Aspirin therapy

Bujold et al : J Obstet Gynecol Can 2009; 31(9):818-826Metaanalysis of 9 randomised studies on basis of abnormalUTA Doppler Low-dose-Aspirin started :

< or 16 weeks : Relative risk (RR) 0.48; 95%CI (0.33-0.68)

17-19 weeks : Relative risk (RR) 0.55; 95%CI (0.17-1.76)

> 20 weeks : Relative risk (RR) 0.82; 95% CI ( 0.62-1.09 )

UTA Doppler in non-invasive assessment of therapeutical effect of

nitric oxide donors in severe PE

Impaired Endothelial Nitric oxide Release in PE

ACH

Impaired vascular relaxation

Sodium Nitroprusside (NO donor)

Vascular relaxation Restored

McCarthy et al, AJOG 1993

NITRIC OXIDE & PLATELETS

NO

Inhibits Aggregation

Inhibits Adhesion

Inhibits Activation

Promotes Disaggregation

Trapani A et al: Transdermal nitroglycerin (GTN) patch in patients with severe PE : effect on UTAPI,UMAPI and MCAPI values.UOG 2011; 38:389-394* Prospective study, 30 pregnant women (24-31 wks of gestation)* Severe PE , abnormal UMAPI and UTAPI values* Transdermal GTN patch (average dose 0.4mg/h) for 3 days

Results :* Significant reduction of UTAPI values(25.3+/-4.9%; p<0.001 )* Significant reduction of UMAPI values(23.1+/-6.9%; p<0.001)* No significant changes in MCAPI values* The mean arterial blood pressure decreased from 119.5+/-4.5mmHg to 114.8+/- 4.4 mmHg( p< 0.05)

Double-blind, randomized, placebo-controlled study will be soon published

Conclusions :

* PE is one of the leading causes of maternal and perinatal morbidity and mortality.

UTAD is a promising technique for predicting PE , however has low sensitivity and predictive validity.

More attention need to be focused on combined screening for PE , including maternal risk factors, UTAD, and biochemical markers , to improve the predictive validity of the test.

* Uterine artery Doppler fulfils almost all the criteria required for efficient prenatal screening test.

* Low dose aspirin appears to be effective in preventing severe PE when administered before 16 weeks gestation.

* Nitric Oxide donors appear to be safe and effective in treating severe PE and may be valuable in long term prophylaxis.

THANK YOU

Randomised placebo controlled trial of vitamin C and E for prevention of PE in high-risk women

St.Thomas Hospital, London, 20062395 patients : 1196 allocated to vitamins C and E1205 allocated to placebo

Results :

* No reduction of PE frequency (15% vs.16%)* More SGA neonates (<2500g) were born to women randomised to receive vitamins C and E (28% vs 24%)* No difference in the rate of SGA < 5th centile* The number of stillbirths >24 weeks gestation was higher in women receiving vitamins C and E RR 2.70; 95%CI(1.02-7.14 )

“ The likelihood of developing pre-eclampsia is increased in women who are :

*nulliparous*aged 30 years or over*those with a prior or a family history of PET*those with a BMI of 35 or above*and those with pre-existing vascular disease”

Antenatal care : routine care for the healthy pregnant woman, NICE guideline 6 , 2006

The best screening tests have to be :

* accessible * safe* relatively inexpensive* acceptable to patients* reproducible results* easy to perform with training and experience

McLeod L : CMAJ 2008; 178 : 727-732