predictive values with/without notches for all complications harrington k et al uog 1996 sensiti-...
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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
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