Clinical significance of the uterine artery Doppler flowmetry : state of the art

1. Clinical significance of the uterine artery Doppler flowmetry: state of the art

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

3. 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

4. PerinatalmortalityFetal abnormalitiesPremature birth Impaired placentationAccount for more than 90 % of perinatal deaths

5. 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

6. KEY vessel for prediction of pre-eclampsiaUTERINE ARTERY

7. 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

9. Predictive Values with/without notches for all complicationsHarrington K et al UOG 1996 * Any complication: PPIH, SGA <10th, placental abruption, stillbirth/NND ** Severe complications: PPIH prior to 37 wks, SGA < 3rd, plac.abruption, still birth

10. False Positive Rate = 5% Martin 2001, Papageorghiou 2001

11. The future : First trimester screening for PE

12. Early biomarkers to predict PE * Angiogenic proteins : VEGF, PIGF* Anti-angiogenic proteins : SFLT 1, s-Endoglyn* PAPP-A* PP 13* Inhibin A , Activin A

13. Sensitivity for Predicting early onset PE with different FPR using BCH markers and UTAPI 8366 women; 165 PE (20%); 37 early onset PE (0.4%). K. Nicolaides Data ( Cuckle, UOG 2011)

14. Prevention of Pre-eclampsia UTA Doppler as non-invasive tool for monitoring of therapeutical effect in PE

15. Agents that have been tried: HeparinLow-dose Aspirin Nitric oxide SteroidsFish oilAntioxidants(vit. E)MagnesiumCalciumYellow = some benefit Red = potentially dangerous

16. Low dose Aspirin therapyBujold et al : J ObstetGynecol 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 )

17. UTA Doppler in non-invasive assessment of therapeuticaleffect of nitric oxide donors in severe PE

18. Impaired Endothelial Nitric oxide Release in PE Sodium Nitroprusside (NO donor) ACH Impaired vascular relaxation Vascular relaxation Restored McCarthy et al, AJOG 1993

19. NITRIC OXIDE & PLATELETS Inhibits Aggregation Promotes Disaggregation NO Inhibits Adhesion Inhibits Activation

20. 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 daysResults :* 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

21. 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.

22. * 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.

24. THANK YOU

25. Randomised placebo controlled trial of vitamin C and E for prevention of PE in high-risk womenSt.Thomas Hospital, London, 20062395 patients : 1196 allocated to vitamins C and E1205 allocated to placebo

26. 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 )

28. “ 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

29. The best screening tests have to be :* accessible * safe* relatively inexpensive* acceptable to patients* reproducible results* easy to perform with training and experienceMcLeod L : CMAJ 2008; 178 : 727-732